MichaЕ‚ englert

MichaЕ‚ Englert

MichaЕ‚ Englert -

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Login to create it. Global s focus the search bar. On all edit pages t open translation selector. The Horse Boy … Director of Photography.

The Other Lamb … Director of Photography. Nightwalk … Camera Operator. She was born on Sunday May 4th , in Warsaw, Poland,.

Michal Englert is practical, down to earth with strong ideas about right and wrong. She is orderly, organized, systematic and controlled, and once committed - she employs decisive and methodical steps to problems solving, without giving up easily.

Michal seeks to establish a solid foundation, and would rather use hard work and long hours to build a business or career than search for "get rich quick" schemes.

She has great potential for success, but only after putting out effort and overcoming the limitations she so often encounters.

Courageous and a true survivor, she is a builder and the foundation of any enterprise, and her hard work and practical values pay off to provide Michal Englert with the rewards she seeks and deserves.

Justice and honesty are sacred to Englert, making her reliable and dependable, and quite often - a cornerstone in the community.

Also, though not a typical idealist, Michal Englert is willing to work for a better world in a realistic way.

Michal Englert works well with others, but it is important that she would have her own responsibility and well-defined task, because she performs better when her responsibilities are not overlapping with those of others.

Due to the rare discipline and perseverance that Englert possesses, not everyone can keep up with her, and she has to be careful not to be bossy and rude.

She can be also rigid in her ideas and get stuck in convention or too quick in judging her fellow man. Michal Englert is loyal to those she loves.

She is well suited for marriage and often becomes a responsible loving parent. However, anything that violates her profound sense of order, such as separation or divorce can be a shattering experience for her.

More flavors to Michal's personality Entrepreneurial and progressive, Michal Englert is ever-striving, heading for the top, and enjoying an enterprising, ambitious and determined personality to do things well, and an unyielding dedication to her plan until the goals are achieved.

She bounces back easily from setbacks and can overcome any adversities or obstacles thrown in her way.

BAV, coarctation of the aorta, and systemic hypertension are associated with aortic dilatation and dissection. The exact genetic abnormality found on karyotype analysis varies and can include classic 45,X but also individuals who are mosaic 45,X with another cell line, including 46,XX, 47,XXX, or 46,XY, as well as individuals with structural abnormalities of the X chromosome, including deletions and translocations of the X chromosome.

Array CGH is useful to define precisely the extent of the deletions or translocation. For mosaic individuals, the phenotype is generally less severe as the percentage of 45,X cells decreases.

It is important to determine whether there are any cells with a Y chromosome using an SRY polymerase chain reaction test, because this can be associated with gonadal dysgenesis that might require surgical removal of gonadal tissue to prevent the increased risk of cancer.

CNVs range widely in size from single genes to large segmental deletions or duplications of millions of base pairs. In general, deletions are more deleterious than duplications because of the sensitivity in gene dosage for many genes that do not tolerate haploinsufficiency.

CNVs that encompass multiple genes can have a wide range of phenotypic effects because of the additive impact of individual genes on individual phenotypes or the pleiotropic effects of single genes on multiple phenotypes.

Identification of the relevant gene for congenital HD within a CNV interval requires mapping of multiple patients with overlapping CNVs to identify a critical interval and ultimately a single gene within the critical interval that is associated consistently with congenital HD.

Additional supportive evidence for the congenital HD gene is provided by examples of patients with point mutations within that single gene within the critical region who have congenital HD.

At least part of the explanation for the worse outcome could be an association with extracardiac manifestations that impact medical care.

In one series of 58 patients with congenital HD and other dysmorphic features or other anomalies, Many new CNVs associated with congenital HD have been identified over the past 10 years and now have been observed in sufficient numbers of patients to define the clinical features associated with them.

There are several common principles that apply across the CNVs. Each of the CNVs includes contiguous gene deletions or duplications, and generally deletions are associated with greater severity of neurocognitive phenotype.

Because each of the CNVs includes multiple genes, it is not always clear whether the overall phenotype is caused by the effects of multiple genes on multiple aspects of the phenotype or whether certain single genes within the interval have pleiotropic effects on multiple aspects of the phenotype.

It is usually unclear what the other determinants of congenital HD are, but it is likely that they are interacting with genetic factors either on the opposite allele or genetic variants in cis on the same chromosome or in trans on other chromosomes, as well as nongenetic factors.

Most CNVs are associated with effects on behavior and cognition, and many are associated with growth effects that are independent of the congenital HD and are important to appreciate when assessing clinical outcomes.

In this section, several CNVs are highlighted. The Appendix provides information on other less frequent CNVs.

The 22q Frequent clinical features include dysmorphic facies, congenital HD especially conotruncal malformations and aortic arch anomalies , palatal malformations, learning difficulties, and immunodeficiency.

Facial features are characteristic but can be relatively subtle, especially in infants. Facial dysmorphisms include myopathic facies, tubular nose with bulbous nasal tip, hypoplastic alae nasi, and low-set or dysplastic ears.

Additional findings include hypocalcemia, significant feeding and swallowing problems including regurgitation through the nose , constipation, renal anomalies, hearing loss, laryngotracheoesophageal anomalies, growth hormone deficiency, autoimmune disorders, seizures, central nervous system anomalies, skeletal abnormalities, ophthalmologic abnormalities, enamel hypoplasia, and malignancies rare.

Behavioral and learning disabilities become more evident in school-aged children, whereas psychiatric disorders often become manifest in adolescence and adulthood Table 2.

Delays in emergence of language, intellectual disability, and learning differences nonverbal learning disability with verbal IQ significantly greater than the performance IQ are common.

Attention deficit disorder, anxiety, perseveration, and difficulty with social interactions are also common. The estimated prevalence of the 22q The majority of 22q It is important to identify the cardiac patient with a 22q For example, there is a higher operative mortality in some patients with 22q Affected individuals should receive leukocyte-depleted and cytomegalovirus-negative blood products to prevent serious graft-versus-host disease or overwhelming infection.

Given the frequency of 22q Clinical assessment for syndromic features alone might not consistently identify the infant carrying a 22q11 deletion, because facial features can evolve with time.

Therefore, routine screening of individuals with selected types of congenital HD using CMA is warranted either prenatally or postnatally.

The estimated 22q Among those with tetralogy of Fallot, the strongest association with 22q Aortic root dilation has been described with 22q Deletion of several genes within this region contributes to the cardiac and noncardiac features.

The size of the deletion can be precisely determined by CMA. Smaller or larger deletions can contribute to atypical clinical phenotypes.

Mutations outside the interval or on the nondeleted 22q An example of this is Bernard-Soulier syndrome, an autosomal recessive trait, which includes giant platelets, thrombocytopenia, and a prolonged bleeding time.

Several cases of Bernard-Soulier syndrome have been reported in which a 22q Although rare, the occurrence of these 2 conditions together can potentially place the 22q Duplication of the same 22q Generally, the duplication is associated with milder and more variable manifestations than the deletion.

The duplication can be either de novo or inherited from a phenotypically normal parent. Many of the reported series likely suffer from ascertainment bias compared with phenotypes in unselected population-based cohorts.

A small number of individuals have distal deletions of 1. Patients with the distal deletion share some overlapping neurobehavioral features, including speech delay and learning disabilities, with proximal 22q A recent study compared rare CNVs outside the common 22q Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q Williams-Beuren syndrome or Williams syndrome WS is a contiguous gene deletion syndrome caused by deletion at 7q Feeding difficulties during infancy often lead to poor weight gain.

Adults have short stature less than third percentile and tend to be overweight or obese and to have complications of systemic hypertension, diabetes mellitus, and diverticulosis.

Frequent cardiovascular anomalies include supravalvular aortic stenosis SVAS , often in combination with supravalvular pulmonary artery stenosis and branch pulmonary artery stenosis.

The SVAS can progress during childhood and is the most common abnormality requiring surgical intervention. In contrast, the branch pulmonary artery stenosis often regresses with time.

Any artery can be narrowed, including the ascending aorta, aortic arch, and descending thoracic and abdominal aorta, as well as central and peripheral arteries including the coronary arteries, carotid and cerebral arteries, mesenteric arteries, renal arteries, and pulmonary arteries.

Affected arteries typically have thickened walls and narrowed lumens. There is an increased risk of anesthesia-related complications and sudden cardiac death.

Risk factors include myocardial ischemia attributable to coronary stenosis or severe biventricular outflow tract obstruction, but the causative mechanisms have not been fully delineated.

As with other contiguous gene deletion syndromes, WS has a broad range of phenotypic variability. Although there is wide phenotypic variability even among individuals with the typical deletion, smaller or larger deletions might contribute to atypical clinical phenotypes.

Given the clinical variability of WS and the fact that the physical and developmental signs can be relatively subtle during infancy, it is not unusual for the diagnosis to be confirmed only after identification of a characteristic cardiovascular defect such as SVAS.

The severity of SVAS and other vascular defects tends to be greater in males, and infants and children with more severe vascular involvement tend to be diagnosed with WS at younger ages than those with trivial or no cardiovascular involvement.

Because SVAS is very common in WS and uncommon in the general population, it is appropriate to consider testing all patients with SVAS at the time of diagnosis of the cardiovascular defect.

Furthermore, if peripheral pulmonary artery stenosis persists beyond infancy, it is also appropriate to consider testing for WS.

Similarly, if any of the defects associated with the elastin arteriopathy, including coronary artery ostial stenosis, renal artery stenosis, and middle aortic syndrome abdominal coarctation , are diagnosed at any age, testing for WS should be considered.

Of note, CNVs in the 7q Early diagnosis of WS is important to optimize management of other potential medical problems Table 4.

Hypercalcemia occurs most commonly in the first year of life, whereas hypercalciuria can persist and occur at any age.

Hypercalcemia can lead to nephrocalcinosis and renal failure. Obesity, abnormal oral glucose tolerance tests, and diabetes mellitus are common, especially in adults.

Intellectual disability is common and usually mild, but with a specific cognitive profile with strengths in verbal short-term memory and language and extreme weakness in visuospatial constructive cognition.

Attention deficit disorder and anxiety are common. JS is a clinically recognizable contiguous gene deletion syndrome involving deletions from subband 11q23 to the telomere, ranging in size from 7 to 16 Mb.

Clinical manifestations include dysmorphic features, growth retardation sometimes associated with IGF-1 insulin-like growth factor 1 deficiency, cognitive and behavioral dysfunction, congenital HD, thrombocytopenia and platelet dysfunction Paris-Trousseau syndrome , recurrent infections, immune deficiency, and ophthalmologic, gastrointestinal, and genitourinary problems.

A prospective study of patients with the 11q terminal deletion disorder, diagnosed by karyotype rather than CMA, provided detailed delineation of the clinical manifestations, as well as a comprehensive set of recommendations for the clinical management of patients with this disorder.

More than half of affected individuals have congenital HD, most of whom require surgical intervention.

About one-third of patients with heart defects have a membranous VSD, and another third have left ventricular outflow tract defects with various degrees of hypoplasia or obstruction of the mitral valve, left ventricle, aortic valve, or aorta.

The prevalence of JS is estimated to be 1 in to 1 in live births. Through a combination of human genetic techniques and using genetically engineered animal models, ETS1 has been identified as the causal gene for congenital HD in JS.

Most recently, a patient with a complex congenital HD including mitral atresia and hypoplastic left ventricle was found to carry a de novo frameshift mutation in ETS1 , likely a loss-of-function mutation, providing further confirmation that loss of ETS1 is the cause of congenital HD in JS.

There is no correlation between the size of the deletion and whether or not there is congenital HD or what the specific congenital HD is.

Nearly all patients with JS have Paris-Trousseau syndrome, characterized by thrombocytopenia and platelet dysfunction, and heterozygous loss of the FLI1 gene has been identified as the cause.

Platelet dysfunction persists in older individuals, despite normal platelet counts. Risk for bleeding is one of the most common causes of mortality in JS and likely places these patients at increased risk for the development of brain hemorrhages.

Cognitive function ranges from normal intelligence to moderate cognitive disability. Nearly half of the patients have mild cognitive disability, with a characteristic neuropsychiatric profile demonstrating near-normal receptive language ability but mild to moderate impairment in expressive language, with full-scale IQs typically in the 60s to 70s.

Individuals with suspected or confirmed JS should have a thorough genetics evaluation. The extent of the deletion can be precisely delineated by CMA in the proband.

Patients with JS require coordinated multisystem care. A cardiac evaluation including an echocardiogram is recommended at baseline and as needed.

Careful monitoring of the platelet count is necessary in infancy and early childhood, and once the platelet count normalizes, platelet function studies should be evaluated periodically.

Neurocognitive and behavioral difficulties are common. Baseline and ongoing evaluations by a neuropsychologist and behavioral specialist are recommended, as well as brain imaging at baseline and as needed.

Patients should be screened for ophthalmologic issues including exotropia, amblyopia, refractive errors, ptosis, and retinal artery tortuosity.

Common gastrointestinal issues include failure to thrive, constipation, and pyloric stenosis. Genitourinary anomalies include cryptorchidism and renal anomalies.

A baseline renal ultrasound is recommended. The 1p36 deletion syndrome is the second most common deletion syndrome. Clinical features include dysmorphic facies, intellectual disability ranging from mild to severe, hypotonia, seizures, structural brain abnormalities, congenital heart defects, ophthalmologic and vision issues, hearing loss, skeletal abnormalities, and genitourinary anomalies.

Behavioral disorders include autism, tantrums, self-mutilation, stereotypies, and hyperphagia. Structural brain abnormalities include dilation of the lateral ventricles, cortical atrophy, and hypoplasia or agenesis of the corpus callosum.

Seizures are present in approximately half of the individuals with the 1p36 deletion. The prevalence of 1q36 deletion is 1 in to births, with a female-to-male ratio.

This condition is identified by CMA testing. Recurrent 1. The associated psychiatric and behavioral anomalies include autistic spectrum disorder, attention deficit hyperactivity disorder, mood disorder, and sleep disturbances.

The prevalence of the 1q The condition is identified by CMA. The gene responsible for congenital HD within the interval is possibly GJA5, which encodes for a cardiac gap junction protein connexin The reciprocal duplication of 1q There is a tendency toward larger head size.

Some individuals have neurobehavioral manifestations, including intellectual disabilities, developmental delay, expressive language delay, learning disabilities, features of autism, or attention deficit hyperactivity disorder, but others have no neurobehavioral problems.

Deletions of 8p There are also several reported cases of more complex cardiac anatomy including hypoplastic right ventricle, double-outlet right ventricle, and double-inlet left ventricle.

Table 5 can be consulted for details of multiple other genetic syndromes. Alagille syndrome ALGS is an autosomal dominant syndromic disorder characterized by cardiovascular, hepatic, orthopedic, and ophthalmologic complications.

Children with ALGS have a prominent forehead, deeply set eyes, hypertelorism, straight nose with a bulbous tip, and pointed chin.

There is considerable intrafamilial and interfamilial variability in the hepatic complications of ALGS, and some individuals have no detectable liver disease.

The most common complications are chronic cholestasis, elevated liver enzymes, hypercholesterolemia, or liver failure.

The typical pathological finding is paucity of the bile ducts on liver biopsy. Additional complications include Axenfeld anomaly, Rieger anomaly, optic disk drusen, and retinal pigmentary changes.

Less commonly reported skeletal features include hemivertebrae, spina bifida occulta, and rib anomalies.

Two-thirds of those with ALGS have peripheral or branch pulmonary stenosis or other arterial narrowing aortic coarctation, renal artery, middle aortic syndrome, Moya-moya, basilar, and middle cerebral arteries.

There is no known racial or ethnic predilection for ALGS. There is an estimated incidence of to live births.

Overall, there are no differences in the cardiovascular phenotype based on causative gene or mutation type sequence variant versus deletion.

However, there have been 2 variants reported for which affected individuals had cardiac but not liver disease, and further analysis demonstrated that the amount of JAG1 protein produced was more than in other ALGS variants but less than in wild type.

Holt-Oram syndrome HOS is an autosomal dominant disorder often referred to as heart-hand syndrome because of the 2 most common features: congenital HD and radial ray defects.

Radial ray abnormalities can be unilateral or bilateral and, when bilateral, can be symmetrical or asymmetrical.

The penetrance of upper limb anomalies in HOS is complete but ranges from subtle carpal abnormalities without functional consequence only seen by radiogram to complete phocomelia the hand attached close to the trunk.

Other reported abnormalities include triphalangeal thumb, absent thumb, radius hypoplasia or aplasia, and radioulnar synostosis.

Because there is considerable intrafamilial phenotypic variability, a family history of a first-degree relative with a septal defect, cardiac conduction disease, or radial ray abnormality can provide a clue to the diagnosis.

Three quarters of those with HOS have congenital HD, most commonly involving the atrial or ventricular septum.

ASDs can present as common atrium, often with atrial isomerism. Sinus bradycardia, first-degree atrioventricular heart block, and complete heart block with or without atrial fibrillation are all reported coincident with or subsequent to the time of congenital HD diagnosis if present.

HOS has an estimated prevalence of between 0. TBX5 is a transcription factor and is an essential regulator of limb and cardiac development, particularly the cardiac septum and conduction system.

Flat midface, flat nasal bridge, broad nasal tip, hypertelorism, down-slanting palpebral fissures, mild ptosis, short philtrum, and everted lips are among the recognizable facial features.

Aplasia or hypoplasia of the middle phalanges of the fifth fingers is part of the diagnostic triad along with typical facial features and PDA of Char syndrome.

Case reports indicate a number of additional features can be seen in Char syndrome, including hypodontia, foot anomalies joint fusion, clinodactyly, polydactyly, syndactyly , strabismus, and other hand anomalies interstitial polydactyly, distal symphalangism of the fifth fingers, and third finger hypoplasia.

The primary cardiac finding is PDA. The prevalence has not been determined, but it is thought to be quite rare. Approximately half of families who have the diagnostic triad of Char syndrome recognizable facial features, aplasia or hypoplasia of the middle phalanges of the fifth fingers, and PDA will have a heterozygous pathogenic variant in TFAP2B.

There are no known genotype-phenotype correlations with regard to cardiovascular complications. Ellis-van Creveld syndrome EVC is an autosomal recessive skeletal dysplasia associated with a characteristic cardiac finding of a primary atrial septation defect resulting in a common atrium.

Individuals with EVC can have a characteristic appearance of the mouth, with a short upper lip bound by frenula to the alveolar ridge.

A variety of dental abnormalities are reported, including natal teeth, partial adontia, small teeth, delayed tooth eruption, conical teeth, and enamel hypoplasia.

The nails are often hypoplastic, and hair can be scant or fine. There is prenatal-onset short stature; adult stature is in the range of 43 to 60 inches.

The characteristic skeletal findings include postaxial polydactyly, usually of the hands, short limbs with increasing severity from the proximal to distal portions of the limbs , and short ribs.

Hand radiographs often show short, broad middle phalanges and hypoplastic distal phalanges, and sometimes carpal bone abnormalities.

The worldwide prevalence is not known. There is a founder mutation among the Amish, and large kindreds from Mexico, Ecuador, and Brazil that have also been reported.

No cardiovascular genotype-phenotype correlations have been reported. Adams-Oliver syndrome AOS is an inherited malformation syndrome in which cardiac, scalp, and limb defects are present.

There is genetic heterogeneity, with both autosomal dominant and autosomal recessive forms. There is considerable variability in the extent of aplasia cutis congenita in affected individuals, ranging from total absence of an area of scalp skin and skull to vertex hairless patches.

Limb defects can include terminal transverse reduction defects of hands or feet, short distal phalanges, syndactyly, ectrodactyly, and polydactyly.

There is an estimated incidence of 0. Six genes are currently involved in the pathogenesis of AOS.

Kabuki syndrome KS has both X-linked and autosomal dominant pathogeneses. The syndrome is characterized by specific facial features, skeletal anomalies, congenital HD, renal anomalies, intellectual disability, and growth deficiency.

Children with KS have long palpebral fissures, eversion of lateral one-third of the lower eyelid, arched eyebrows with sparse lateral third, large dysplastic ears, cleft palate, and depressed nasal tip.

There can be associated autism spectrum disorder, communication difficulties, and repetitive behavior.

Cryptorchidism, duplicated collecting system, single fused kidney, and hypospadias have been reported.

The prevalence in Japan was estimated at , as the initial patients described were Japanese. A minimum birth incidence of in Australia and New Zealand has been calculated.

A preponderance of males compared with females with left-sided obstructive lesions has been described among KMT2D patients. The acronymic name of this condition includes C for coloboma, H for heart defects, A for choanal atresia, R for retarded growth and development, G for genital anomalies, and E for ear anomalies.

Diagnostic criteria are helpful in determining a clinical diagnosis for individuals suspected of having CHARGE syndrome.

Characteristic facial features can include orofacial clefts, unilateral or bilateral facial palsy, and malformed protruding ear pinnae. Marked developmental delay is usual.

Motor skills are delayed with hypotonia. Delayed language development can result from hearing loss and reduced vision. Vision is variably affected by the colobomas.

Hearing loss is extremely common and varies from mild to profound. Individuals can have severe swallowing difficulties, aspiration problems, gastroesophageal reflux, and tracheoesophageal fistula.

Feeding problems are very common, and gastrostomy feeding measures are often required. Males can have cryptorchidism and micropenis, and both males and females can have hypogonadotropic hypogonadism.

Hand anomalies including polydactyly and occasional scoliosis are possible. Some families in which there are affected siblings and unaffected parents are likely examples of gonadal mosaicism.

The RASopathies are a group of autosomal dominant disorders with overlapping cardiac, growth, facial, and neurodevelopmental features.

Somatic mutations in genes in the pathway have long been known to cause hematologic cancers and solid tumors. More recently, germline sequence variants have been found to cause Noonan syndrome NS and other uncommon phenotypically related disorders, including cardiofaciocutaneous syndrome CFC , Costello syndrome CS , and Noonan syndrome with multiple lentigines NSML.

Collectively, these disorders are termed the RASopathies. Individuals with NS have characteristic facial features and structural and functional abnormalities involving multiple organ syndromes and a high incidence of cardiac abnormalities.

The facial features of NS change with age. In adulthood, the features are most often mild, although some adults retain significant, readily recognizable dysmorphisms.

Early feeding problems related to hypotonia and delayed gastrointestinal motor development, gastroesophageal reflux, chronic constipation, and intestinal malrotation respond well to medical management and feeding therapy.

The most common endocrine complications include hypothyroidism, pubertal delay, and short stature.

The pathogenesis for the short stature can be nutritional, attributable to growth hormone deficiency, or attributable to growth hormone insensitivity.

Looking across studies, there is a mean gain in height of 9. Coagulation factor deficiencies, thrombocytopenia, and platelet aggregation abnormalities have all been reported ; however, only a small proportion of those with abnormalities on coagulation testing have functional bleeding problems.

NS attributable to PTPN11 mutations is associated with an increased risk of hematologic malignancies, including acute lymphoblastic leukemia and juvenile myelomonocytic leukemia.

It can occur or recur in adolescence or adulthood. Chylous effusion is a regularly reported complication of cardiac surgery.

Less commonly, pulmonary, intestinal, and testicular lymphangiectasia are reported. Gross and fine motor development are often delayed because of hypotonia, congenital HD, or orthopedic issues.

The most commonly reported orthopedic complications include radioulnar synostosis, pectus carinatum and excavatum, scoliosis, and pes planus.

Systematic epidemiological studies have not been completed, but a prevalence of to has been estimated.

NS is an autosomal dominant disorder with complete penetrance and variable expressivity. Fifty percent of cases are explained by heterozygous PTPN11 missense pathologic variants.

In the nonfamilial cases, there is an association with advanced paternal age. They share common features, including developmental delays, short stature, ptosis, hypertelorism, macrocephaly, and cardiac involvement.

There is such significant phenotypic overlap that it can be challenging, particularly during infancy, to make the diagnosis based on clinical features alone.

In contrast to NS, CFC is characterized by more significant feeding issues often requiring long-term gastrostomy tube use and cognitive delays with the majority of individuals in the mild to moderate intellectual disability range and by a variety of cutaneous abnormalities, including hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, and xerosis.

Features most often seen in those with CS but not in NS include coarse facial features, loose and soft skin with deep creases of the palms and soles, bronzing of the skin during childhood, papillomata of the face and perianal region, and an increased risk for malignant tumors.

CS has an estimated birth prevalence of 1 in to 1 in 1 There is a higher prevalence of sensorineural hearing loss and a lower prevalence of short stature than is reported in NS.

Three-fourths of individuals with a RASopathy have a cardiac abnormality, which is the second most common reason a child comes to medical attention after admission to a neonatal intensive care unit.

Gly 12 or p. Gly Potential approaches include single-gene testing, multigene panel testing, and more comprehensive genomic approaches such as whole-exome or whole-genome sequencing.

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Other reported abnormalities include triphalangeal thumb, absent thumb, radius hypoplasia or aplasia, and radioulnar synostosis.

Because there is considerable intrafamilial phenotypic variability, a family history of a first-degree relative with a septal defect, cardiac conduction disease, or radial ray abnormality can provide a clue to the diagnosis.

Three quarters of those with HOS have congenital HD, most commonly involving the atrial or ventricular septum. ASDs can present as common atrium, often with atrial isomerism.

Sinus bradycardia, first-degree atrioventricular heart block, and complete heart block with or without atrial fibrillation are all reported coincident with or subsequent to the time of congenital HD diagnosis if present.

HOS has an estimated prevalence of between 0. TBX5 is a transcription factor and is an essential regulator of limb and cardiac development, particularly the cardiac septum and conduction system.

Flat midface, flat nasal bridge, broad nasal tip, hypertelorism, down-slanting palpebral fissures, mild ptosis, short philtrum, and everted lips are among the recognizable facial features.

Aplasia or hypoplasia of the middle phalanges of the fifth fingers is part of the diagnostic triad along with typical facial features and PDA of Char syndrome.

Case reports indicate a number of additional features can be seen in Char syndrome, including hypodontia, foot anomalies joint fusion, clinodactyly, polydactyly, syndactyly , strabismus, and other hand anomalies interstitial polydactyly, distal symphalangism of the fifth fingers, and third finger hypoplasia.

The primary cardiac finding is PDA. The prevalence has not been determined, but it is thought to be quite rare. Approximately half of families who have the diagnostic triad of Char syndrome recognizable facial features, aplasia or hypoplasia of the middle phalanges of the fifth fingers, and PDA will have a heterozygous pathogenic variant in TFAP2B.

There are no known genotype-phenotype correlations with regard to cardiovascular complications. Ellis-van Creveld syndrome EVC is an autosomal recessive skeletal dysplasia associated with a characteristic cardiac finding of a primary atrial septation defect resulting in a common atrium.

Individuals with EVC can have a characteristic appearance of the mouth, with a short upper lip bound by frenula to the alveolar ridge.

A variety of dental abnormalities are reported, including natal teeth, partial adontia, small teeth, delayed tooth eruption, conical teeth, and enamel hypoplasia.

The nails are often hypoplastic, and hair can be scant or fine. There is prenatal-onset short stature; adult stature is in the range of 43 to 60 inches.

The characteristic skeletal findings include postaxial polydactyly, usually of the hands, short limbs with increasing severity from the proximal to distal portions of the limbs , and short ribs.

Hand radiographs often show short, broad middle phalanges and hypoplastic distal phalanges, and sometimes carpal bone abnormalities. The worldwide prevalence is not known.

There is a founder mutation among the Amish, and large kindreds from Mexico, Ecuador, and Brazil that have also been reported.

No cardiovascular genotype-phenotype correlations have been reported. Adams-Oliver syndrome AOS is an inherited malformation syndrome in which cardiac, scalp, and limb defects are present.

There is genetic heterogeneity, with both autosomal dominant and autosomal recessive forms. There is considerable variability in the extent of aplasia cutis congenita in affected individuals, ranging from total absence of an area of scalp skin and skull to vertex hairless patches.

Limb defects can include terminal transverse reduction defects of hands or feet, short distal phalanges, syndactyly, ectrodactyly, and polydactyly.

There is an estimated incidence of 0. Six genes are currently involved in the pathogenesis of AOS. Kabuki syndrome KS has both X-linked and autosomal dominant pathogeneses.

The syndrome is characterized by specific facial features, skeletal anomalies, congenital HD, renal anomalies, intellectual disability, and growth deficiency.

Children with KS have long palpebral fissures, eversion of lateral one-third of the lower eyelid, arched eyebrows with sparse lateral third, large dysplastic ears, cleft palate, and depressed nasal tip.

There can be associated autism spectrum disorder, communication difficulties, and repetitive behavior. Cryptorchidism, duplicated collecting system, single fused kidney, and hypospadias have been reported.

The prevalence in Japan was estimated at , as the initial patients described were Japanese. A minimum birth incidence of in Australia and New Zealand has been calculated.

A preponderance of males compared with females with left-sided obstructive lesions has been described among KMT2D patients.

The acronymic name of this condition includes C for coloboma, H for heart defects, A for choanal atresia, R for retarded growth and development, G for genital anomalies, and E for ear anomalies.

Diagnostic criteria are helpful in determining a clinical diagnosis for individuals suspected of having CHARGE syndrome.

Characteristic facial features can include orofacial clefts, unilateral or bilateral facial palsy, and malformed protruding ear pinnae. Marked developmental delay is usual.

Motor skills are delayed with hypotonia. Delayed language development can result from hearing loss and reduced vision. Vision is variably affected by the colobomas.

Hearing loss is extremely common and varies from mild to profound. Individuals can have severe swallowing difficulties, aspiration problems, gastroesophageal reflux, and tracheoesophageal fistula.

Feeding problems are very common, and gastrostomy feeding measures are often required. Males can have cryptorchidism and micropenis, and both males and females can have hypogonadotropic hypogonadism.

Hand anomalies including polydactyly and occasional scoliosis are possible. Some families in which there are affected siblings and unaffected parents are likely examples of gonadal mosaicism.

The RASopathies are a group of autosomal dominant disorders with overlapping cardiac, growth, facial, and neurodevelopmental features.

Somatic mutations in genes in the pathway have long been known to cause hematologic cancers and solid tumors. More recently, germline sequence variants have been found to cause Noonan syndrome NS and other uncommon phenotypically related disorders, including cardiofaciocutaneous syndrome CFC , Costello syndrome CS , and Noonan syndrome with multiple lentigines NSML.

Collectively, these disorders are termed the RASopathies. Individuals with NS have characteristic facial features and structural and functional abnormalities involving multiple organ syndromes and a high incidence of cardiac abnormalities.

The facial features of NS change with age. In adulthood, the features are most often mild, although some adults retain significant, readily recognizable dysmorphisms.

Early feeding problems related to hypotonia and delayed gastrointestinal motor development, gastroesophageal reflux, chronic constipation, and intestinal malrotation respond well to medical management and feeding therapy.

The most common endocrine complications include hypothyroidism, pubertal delay, and short stature. The pathogenesis for the short stature can be nutritional, attributable to growth hormone deficiency, or attributable to growth hormone insensitivity.

Looking across studies, there is a mean gain in height of 9. Coagulation factor deficiencies, thrombocytopenia, and platelet aggregation abnormalities have all been reported ; however, only a small proportion of those with abnormalities on coagulation testing have functional bleeding problems.

NS attributable to PTPN11 mutations is associated with an increased risk of hematologic malignancies, including acute lymphoblastic leukemia and juvenile myelomonocytic leukemia.

It can occur or recur in adolescence or adulthood. Chylous effusion is a regularly reported complication of cardiac surgery.

Less commonly, pulmonary, intestinal, and testicular lymphangiectasia are reported. Gross and fine motor development are often delayed because of hypotonia, congenital HD, or orthopedic issues.

The most commonly reported orthopedic complications include radioulnar synostosis, pectus carinatum and excavatum, scoliosis, and pes planus.

Systematic epidemiological studies have not been completed, but a prevalence of to has been estimated. NS is an autosomal dominant disorder with complete penetrance and variable expressivity.

Fifty percent of cases are explained by heterozygous PTPN11 missense pathologic variants. In the nonfamilial cases, there is an association with advanced paternal age.

They share common features, including developmental delays, short stature, ptosis, hypertelorism, macrocephaly, and cardiac involvement.

There is such significant phenotypic overlap that it can be challenging, particularly during infancy, to make the diagnosis based on clinical features alone.

In contrast to NS, CFC is characterized by more significant feeding issues often requiring long-term gastrostomy tube use and cognitive delays with the majority of individuals in the mild to moderate intellectual disability range and by a variety of cutaneous abnormalities, including hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, and xerosis.

Features most often seen in those with CS but not in NS include coarse facial features, loose and soft skin with deep creases of the palms and soles, bronzing of the skin during childhood, papillomata of the face and perianal region, and an increased risk for malignant tumors.

CS has an estimated birth prevalence of 1 in to 1 in 1 There is a higher prevalence of sensorineural hearing loss and a lower prevalence of short stature than is reported in NS.

Three-fourths of individuals with a RASopathy have a cardiac abnormality, which is the second most common reason a child comes to medical attention after admission to a neonatal intensive care unit.

Gly 12 or p. Gly Potential approaches include single-gene testing, multigene panel testing, and more comprehensive genomic approaches such as whole-exome or whole-genome sequencing.

Because there is significant genetic heterogeneity for a given diagnosis and extensive phenotypic overlap between diagnoses, multigene panel testing that includes all of the RASopathy genes is likely the most cost-effective and clinically indicated approach.

A molecular genetic diagnosis allows for specific prognosis, anticipatory guidance, and recurrence risk estimates for families.

If not completed already, an evaluation with a cardiologist, including an echocardiogram and ECG, is indicated at the time of diagnosis.

Follow-up is tailored to the individual findings, ideally informed by the spectrum of disease and natural history of cardiac abnormalities in the RASopathies.

If no cardiac disease is detected, repeat evaluation with a cardiologist is indicated every 5 years throughout childhood and adulthood.

Cilia are ancient organelles with a broad range of biological functions that center on sending and receiving signals to and from the extracellular environment.

Abnormal cilia structure and function result in diverse diseases, including syndromic ciliopathies, primary ciliary dyskinesia PCD , and heterotaxy syndrome.

All cilia extend from a basal body and contain doublet microtubules Figure [C]. These doublets extend as the axoneme, a highly ordered arrangement that is recognizable by transmission electron microscopy.

Motile cilia are primarily found on epithelial cells that line the respiratory tract, brain ventricles, and oviducts.

Absence or dysfunction of motile cilia causes PCD. These cilia extend from the surface of almost all cell types in the human body, including epithelial cells lining the kidney tubules and bile ducts, as well as nonepithelial cells such as chondrocytes and neurons.

The central pair is indicated by the yellow arrowhead. Outer dynein arms black arrow and inner dynein arms red arrow are shown linking the 9 sets of microtubule doublets.

Location in the ciliary axoneme in C is indicated. C, Diagrammatic representation of a cilium indicating structures that have been linked to congenital heart disease.

Hh indicates hedgehog. The best understood role for cilia in heart development is establishing left-right LR asymmetry. The heart has striking asymmetries along the LR axis, all of which depend on global LR positional cues that originate from a ciliated LRO early in development, before cardiac morphogenesis.

The LRO is highly conserved among vertebrates and functions through motile LRO cilia to generate directional fluid flow. The precise mechanisms that connect asymmetrical signals to heart development remain unknown.

Finally, asymmetrical left-sided signals are constrained by a midline barrier. Beyond their role at the LRO in establishing LR asymmetry, cilia are found in cardiac tissue, including the second heart field, where cilia are required for signaling via the sonic hedgehog pathway.

Cilia are also found on embryonic myocardial cells, in mesenchymal cells in the developing AV valves, and in the developing vasculature.

Heterotaxy, from the Greek heteros different and taxis arrangement , refers to any placement of organs along the LR axis that deviates from complete situs solitus and complete situs inversus and includes left atrial isomerism LAI and right atrial isomerism RAI.

In both LAI and RAI, the liver is located at the midline, and abnormal positioning of the gall bladder and stomach is common. Abnormalities of spleen number asplenia or polysplenia can result in functional asplenia that requires management.

Gut malrotation poses a risk for volvulus. Extrahepatic biliary atresia is a severe extracardiac complication that affects prognosis and mortality rate.

Central nervous system abnormalities can also be seen. However, the majority of cases of heterotaxy do not occur as part of a larger genetic syndromic condition, and intellectual development is usually normal.

Heterotaxy can be associated with almost all known congenital HD. The most prominent cardiac findings are atrioventricular canal defects that are frequently unbalanced and associated with other congenital HD such as malposed great vessels.

Right ventricular obstruction and anomalous pulmonary venous return are more commonly observed in RAI, whereas left ventricular obstruction, interrupted inferior vena cava, and rhythm disturbances resulting from an absent sinus node are more commonly associated with LAI.

The hallmark of congenital HD in heterotaxy, however, is that there is no absolutely defined pattern to the possible combination of cardiac and vascular defects.

Its incidence could be underestimated because of subtle or clinically insignificant findings of laterality disorders, such as bilateral superior vena cava.

Aneuploidies, complex chromosomal rearrangements, and microdeletions have all been identified in patients with heterotaxy.

Although penetrance is high, at least 1 case of nonpenetrance has been identified. One of the hallmarks of inherited laterality disorders is the broad range of both laterality and cardiac phenotypes that result from any given mutation.

For example, loss-of-function variants in ZIC3 have been correlated with a range of phenotypes ranging from classic heterotaxy with variable extracardiac manifestations to isolated congenital HD.

Kartagener syndrome is a subset of PCD, a disorder defined by abnormal ciliary motility in the airway epithelia.

Chronic wet, productive cough, daily rhinitis, recurrent or chronic bacterial infections of the lower airways, recurrent sinusitis, and otitis media are common features.

Bronchiectasis is seen in adults. Low nasal nitric oxide is a useful marker of PCD, but testing is not reliable in infants and young children.

At least PCD is most commonly inherited as an autosomal recessive condition, although a rare association of X-linked PCD with retinitis pigmentosa has been described and a new X-linked form of PCD has recently been identified.

The number of PCD-causing genes that can also cause isolated congenital HD is unknown, but recent work shows that predicted damaging variants are found in genes required for ciliary motility and function in patients with congenital HD.

Patients with PCD pathogenic variants most commonly present with randomization of situs resulting in situs inversus or situs solitus and only rarely with heterotaxy.

The sensory ciliopathies are a group of genetically and phenotypically heterogeneous disorders caused by abnormalities in the sensory or signaling functions of cilia.

They are inherited in an autosomal dominant, autosomal recessive most common , or X-linked pattern. Organs most commonly affected are those in which nonmotile sensory cilia play important roles, such as the eyes, ears, skeleton, brain, kidney, and liver.

Retinitis pigmentosa and cone-rod dystrophy are common eye findings. Sensorineural hearing loss occurs in a variety of ciliopathies.

Structural defects have been described, including the classic brain stem malformations molar tooth sign in Joubert syndrome, Dandy-Walker malformation, and neural tube defects, including encephalocele, holoprosencephaly, and agenesis of the corpus callosum.

Diabetes mellitus is the most common endocrine abnormality. Dwarfism, thoracic dysplasia, short limbs, and polydactyly characterize a variety of ciliopathies, some of which are perinatal lethal.

Four groups with major skeletal involvement include the cranioectodermal dysplasias, the short-rib thoracic dysplasias, EVC, and the oral-facialdigital syndromes.

Prototypical features are hepatic fibrosis and hepatic cysts. Liver disease in ciliopathies is not a primary disease of the hepatocytes but rather is a developmental defect of the portobiliary system.

Polycystic kidneys are common features of many ciliopathies. Nephronophthisis is characterized by renal cysts, tubular basement membrane disruption, and tubulointerstitial fibrosis.

In addition to situs abnormalities of the heart, atrioventricular canal defects, septal defects, and valve defects can occur with reduced penetrance.

The mechanistic basis of the congenital HDs has not yet been established for each syndrome. Findings of laterality defects should reflect disruption of LRO function, whereas isolated congenital HDs might result from abnormalities of cilia within the heart.

Cardiomyopathy is identified in Alstrom syndrome. The prevalence varies by syndrome subtype, but all syndromes are quite rare, with estimates ranging from to There are examples of founder effects, with the incidence of Meckel-Gruber as high as in some populations Finnish.

As seen in Table 7 , several of the disorders have allelic overlap. For example, Joubert syndrome and Meckel-Gruber syndrome share many of the same genetic causes.

How the same allele causes disparate phenotypes for many of the ciliopathies is not fully apparent. For the multisystem disorders, specific organ involvement or severity can correlate with the particular gene involved.

For example, in a patient with Joubert syndrome, pathogenic variants in NPHP1 , a gene that can also cause nephronophthisis, are more likely to be found in association with renal involvement.

Modifier alleles and digenic inheritance have been described, and these presumably affect phenotypic presentation. In some cases, the variant type eg, loss of function versus missense will dictate presentation.

Genotype-phenotype correlations have not been described for cardiac presentations. Studies of the mouse model predict that ciliary defects will be identified that cause recessively inherited isolated congenital HD in the absence of a syndromic ciliopathy or PCD, and recent studies show an over-representation of rare, predicted damaging variants in recessive genes in patients with isolated congenital HD versus control subjects.

Recent work on large cohorts of patients with severe mitral valve prolapse identified that mutations affecting DCHS1 are linked to congenital mitral valve defects, and DCHS1 localizes to the base of the ciliary apparatus.

In the future, genomic analyses of large cohorts of congenital HD will likely yield additional cilia genes with a role in congenital HD and begin to establish more focused genotype-phenotype correlations.

Clinical genetic testing is directed on the basis of the differential established through medical history, including family history, and physical examination.

All patients with heterotaxy should have CMA because of associations with chromosome abnormalities and pathogenic CNVs. In addition, strong consideration should be given to ZIC3 testing, particularly in males with heterotaxy.

Recurrence risk estimates are substantially impacted by test results. Although additional studies are necessary to further establish the prevalence of PCD in patients with heterotaxy, consideration should be given to evaluation for PCD, because respiratory and pulmonary management could be optimized to improve the higher than expected surgical morbidity and mortality in this patient group.

Concern for syndromic ciliopathies should prompt molecular testing for these disorders via ciliopathy panels or exome sequencing.

One of the challenging aspects of caring for patients requiring surgical repair of congenital HD is the variation in postoperative outcomes even for patients with anatomically and physiologically identical congenital HD.

Respiratory complications are one of the most important modulators of postoperative outcome that can be influenced by genetic pathogenesis of the congenital HD.

If patients at increased risk for respiratory and other complications can be identified preoperatively, it might be possible to modify their care and improve clinical outcomes.

Pathological variants in ciliary genes are known to cause heterotaxy, some types of nonheterotaxy congenital HD, , and PCD.

With this in mind, it is not surprising that patients with congenital HD, heterotaxy, and associated airway ciliary dysfunction have a higher rate of respiratory complication postoperatively than similar patients without airway ciliary dysfunction.

As discussed earlier, numerous genes have been implicated in the pathogenesis of congenital HD when it occurs in the setting of a genetic syndrome, but the identification of the genetic contributors of nonsyndromic congenital HD has proved to be more challenging.

Although initial insights were based on studies of large, multigenerational kindreds in which multiple family members were affected with a cardiac malformation, these families are relatively uncommon, and the congenital HD is often less severe.

Establishing disease causality, especially of a specific variant, remains a challenge. These genes mostly encode transcription factors, signaling molecules, or structural proteins important in cardiac development, structure, and function.

Detailed information about the associated cardiac phenotypes and references to supporting studies are reviewed in Anderson et al and Fahed et al and are provided in Table 8.

Many of the congenital HD genes identified to date can be assigned to one of the following functional categories. Initial insights into the genetic pathogenesis of non-syndromic congenital HD were based on the discovery of disease-causing sequence variants in critical cardiac transcription factors identified as important for normal heart development in multiple animal model systems.

A similar approach identified heterozygous mutations in GATA4 , a gene encoding another important cardiac transcription factor, in familial congenital HD.

Evidence supporting these genetic associations has come from analysis of mice haploinsufficient for Gata4 or harboring disease-causing Gata4 mutations.

These mouse models have replicated human disease phenotypes. Another important transcription factor family linked to congenital HD is the Tbox family.

Other cardiac transcription factors implicated in congenital HD pathogenesis are listed in Table 8. Garg et al reported a multigeneration family with autosomal dominant cardiovascular disease in which 9 members had aortic valve disease, primarily BAV, but also 1 member with tetralogy of Fallot.

Given the large number of genes that contribute to congenital HD, NGS is being increasingly used in both research and clinical settings in congenital HD patients.

In one of the earliest studies led by the Pediatric Cardiac Genomics Consortium that used WES in severe congenital HD cases parent-offspring trios , congenital HD cases showed a significant excess of proteinaltering de novo sequence variants in genes expressed in the developing heart, with particular enrichment of histone-modifying genes that regulate expression of key developmental genes.

The same group performed exome sequencing of congenital HD parent-offspring trios and identified an excess of protein-damaging de novo variants in genes highly expressed in the developing heart and brain.

These findings revealed shared genetic contributions to congenital HD, neurodevelopment, and extracardiac anomalies. A large international study using WES of probands found a significant enrichment of de novo protein-truncating variants but not inherited protein-truncating variants in known congenital HD genes in syndromic congenital HD.

Conversely, in nonsyndromic congenital HD, there was a significant enrichment of protein-truncating variants inherited from unaffected parents in congenital HD genes.

This study underscored the distinct genetic architectures of syndromic versus nonsyndromic congenital HD.

Finally, a recent study using mouse forward genetics identified sequence variants in novel genes not previously associated with congenital HD, Sap and Pcdha9 , as being digenic causes of HLHS.

Sap mediated left ventricular hypoplasia, whereas Pcdha9 increased penetrance of aortic valve abnormalities. There are several hundred genes that either cause or contribute to congenital HD.

Sequence variants in congenital HD genes can cause both sporadic and inherited congenital HD. Sequence variants in congenital HD genes can cause both syndromic and nonsyndromic congenital HD, with strong association of de novo variants with syndromic CHD and of inherited variants with nonsyndromic congenital HD.

There is phenotypic heterogeneity, with sequence variants in the same genes often associated with different cardiac phenotypes, not only between families but also within families.

Family studies often show incomplete segregation even in familial congenital HD, with could be attributable in part to incomplete penetrance but could also be related to oligogenic origins of congenital HD.

The above findings have clinical implications. Although several laboratories offer congenital HD gene panels of various sizes for clinical testing, the relatively large numbers of genes involved and the role of novel and ultra-rare variants in causing rare disorders coupled with the oligogenic origins of some of the more complex congenital HDs suggest that a genome-wide search for congenital HD—associated variants might be cost-effective in the future as the accuracy of variant interpretation improves.

Experience, challenges, and cost-effectiveness of clinical exome sequencing have been reported recently. Widespread exome and genome sequencing of congenital HD patients is uncovering an ever-increasing number of candidate disease genes and disease-causing variants.

Several in vitro and in vivo model systems are available, each with its own strengths and weaknesses.

Recently, in vitro strategies have been developed in cell and tissue engineered models that complement the animal models and facilitate mechanistic studies.

These key features have made the murine system the most widely studied animal model of cardiovascular development. The mouse genome can be modified by many techniques.

These can be grouped into methods that randomly insert DNA sequences into the genome transgenesis and those that modify an endogenous locus targeted mutagenesis.

Transgenesis, performed by introduction of foreign DNA using a targeting vector into a fertilized oocyte, is most commonly used to direct expression of a gene in an altered form or at an ectopic time, location, or level.

The targeting vector used to modify the endogenous locus can be engineered to inactivate the gene knockout , to introduce recombinase sites into the gene so that it can be conditionally inactivated by a second recombinase allele eg, flank gene with loxP sites [floxed] that can be excised at a specific time in a specific tissue by Cre recombinase , or to modify the endogenous gene knockin.

These techniques for modifying the mouse genome have been used to study cardiovascular development and disease in a number of ways.

The opposite loss-of-function strategy is achieved by constitutive gene knockout or by excising an essential portion of a floxed gene of interest using Cre recombinase, expressed from a transgene or knocked into a second locus so that it is expressed in a known spatiotemporal domain.

Gene knockout approaches have traditionally focused on coding regions. However, this strategy will also be useful to test the functional importance of conserved transcriptional regulatory elements that have been linked to congenital HD causation using high-throughput mapping technologies.

Because reporter activation involves modification of the genome, it is transmitted to all of the progeny of the Cre-expressing cells.

Lineage tracing has been critical to deduce the developmental events that generate the heart, including the contributions of the second heart field, which adds cells onto the arterial and venous ends of the linear heart tube to form parts of the atria and most of the right ventricle and outflow tract, as well as the contribution of the dorsal mesenchymal protrusion to form portions of the atrioventricular septae at the crux of the heart.

Because of practical considerations, congenital HD gene defects are often modeled in mice as homozygous gene knockouts, whereas most congenital HD mutations are heterozygous point or truncating mutations.

Biologically, gene dosage and redundancy are important factors that influence the expression of mutations, and these parameters often vary between species.

For instance, haploinsufficiency of TBX1 in 22q11 deletion syndromes is an important contributor to congenital HD ; however, Tbx1 haploinsufficiency is well tolerated in mouse models, and a more severe reduction of Tbx1 dosage is required to produce cardiac defects.

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