Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.

Fetal Diagnosis of Supravalvular Aortic Stenosis and Pulmonary Stenosis in a Family with Non-Syndromic Elastin Mutation.

Supravalvular aortic stenosis (SVAS) has been well described in Williams-Beuren Syndrome and non-syndromic elastin (ELN) mutations. Non-syndromic ELN mutations are inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity. ELN haploinsufficiency leads to progressive arteriopathy, typically affecting the aortic sinotubular junction. Multi-level pulmonary stenosis has also been reported and biventricular obstruction may portend a worse prognosis. Fetal presentation of ELN mutation with SVAS has not been previously reported in the literature. We present a case of fetal diagnosis of SVAS and multi-level pulmonary stenosis in a family with a known pathogenic ELN mutation (Exon 6, c.278del [p.Pro93Leufs*29]). On the fetus' initial fetal echo, there was only mild flow acceleration through the aortic outflow tract, however, she went on to develop progressive bilateral obstruction. In the early post-natal period, the child was clinically asymptomatic and showed similar mild SVAS and mild valvar and supravalvular pulmonary stenosis. Our case highlights the need for serial monitoring of fetuses with suspected or confirmed ELN arteriopathy.

Cardiovascular Characteristics and Progressions of Hypertrophic Cardiomyopathy and Pulmonary Stenosis in RASopathy Syndrome in the Genomic Era.

INTRODUCTION: To investigate cardiovascular characteristics and progressions of hypertrophic cardiomyopathy (HCM) and pulmonary stenosis (PS) and determine whether any genotype-phenotype correlations exist in patients with gene-confirmed RASopathy syndrome. STUDY DESIGN: Eighty patients (male, 55%) confirmed as having RASopathy syndrome by genetic testing at a single tertiary center were enrolled. Subjects' medical and echocardiography records were reviewed and the changes in the z scores of left ventricular wall thickness (LVWT) and the degree of PS over time were examined during follow-up of 5.7 ± 3.1 and 7.5 ± 5.2 years, respectively. RESULTS: The most common RASopathy gene identified was PTPN11 (56%), followed by RAF1 (10%). Eighty-five percent of patients had cardiovascular diseases, wherein 42% had HCM, and 38% PS. Mean maximal LVWT z score on the initial echocardiography (mean age 5.0 ± 6.0 years) was 3.4 ± 1.3 (median 2.8, range 2.1-6.6) in the HCM group. Overall, the maximal LVWT increased with time, especially in the HCM group (z = 3.4 ± 1.3 to 3.7 ± 1.6, P = .008) and RAF1-variant group (z = 3.7 ± 1.7 to 4.6 ± 1.8, P = .031). Five patients newly developed HCM during the study period. Genotype-phenotype correlation was significant for HCM (P = .002); 31% of patients with PTPN11 and 88% with RAF1 variants had HCM. PS did not progress in this study cohort. CONCLUSIONS: In this study, progression of ventricular hypertrophy was seen in a significant number of patients with genotype correlation. Thus, long-term follow up of cardiovascular problems in patients with RASopathy is necessary.

Cardiac features of Noonan syndrome in Japanese patients.

BACKGROUND: Cardiovascular disease is one of the most important problems in long-term follow-up for Noonan syndrome. We examined cardiovascular issues and clinical manifestations, with a focus on the cardiovascular disease and prognosis of patients with Noonan syndrome. METHODS: This single-centre study evaluated patients who were clinically and genetically diagnosed with Noonan syndrome. RESULTS: Forty-three patients diagnosed with Noonan syndrome were analysed. The most prevalent responsible mutation was found in PTPN11 (25/43). The second and third most prevalent causative genes were SOS1 (6/43) and RIT1 (5/43), respectively, and 67.4% of genetically diagnosed patients with Noonan syndrome had structural cardiovascular abnormalities. Pulmonary valve stenosis was prevalent in patients with mutations in PTPN11 (8/25), SOS1 (4/6), and RIT1 (4/5). Hypertrophic cardiomyopathy was found in two of three patients with mutations in RAF1. There was no difference in the cardiovascular events or cardiovascular disease prevalence in patients with or without PTPN11 mutations. The proportion of RIT1 mutation-positive patients who underwent intervention due to cardiovascular disease was significantly higher than that of patients with PTPN11 mutations. Patients who underwent any intervention for pulmonary valve stenosis exhibited significantly higher pulmonary flow velocity than patients who did not undergo intervention, when they visited our hospital for the first time. All patients who underwent intervention for pulmonary valve stenosis had a pulmonary flow velocity of more than 3.0 m/s at first visit. CONCLUSIONS: These findings suggest that genetic information can provide a clinical prognosis for cardiovascular disease and may be part of genotype-based follow-up in Noonan syndrome.

Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies.

The RASopathies are a group of similar genetic syndromes with cardiovascular abnormalities, characteristic facial features, short stature, abnormalities of the skin and musculoskeletal system, and variable neurodevelopmental challenges. The most common cardiovascular abnormalities include pulmonary valvular stenosis and hypertrophic cardiomyopathy. Congenital polyvalvular disease (CPVD) refers to congenital dysplasia of two or more cardiac valves. We diagnosed a RASopathy in two individuals with CPVD and noted that CPVD in RASopathies has rarely been reported in the literature. Thus, we performed a retrospective chart review and literature review to investigate the association and characterize the phenotype of CPVD in the RASopathies. CPVD was present in 2.5% (n = 6/243) of individuals in our RASopathy cohort. Involvement of two cardiac valves, commonly the aortic and pulmonic valves, was seen in the majority of individuals (6/8; 75%) in our cohort, but only 27% (3/11) of reported CPVD and RASopathy cases in the literature. CPVD should be considered an associated cardiovascular phenotype of the RASopathies, which has implications for diagnosis and management.

Phenotypic delineation of the retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome.

Retinal arterial macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS), also known as Familial Retinal Arterial Macroaneurysms (FRAM) syndrome, is a very rare multisystem disorder. Here, we present a case series comprising ophthalmologic and systemic evaluation of patients homozygous for RAMSVPS syndrome causative IGFBP7 variant. New clinical details on 22 previously published and 8 previously unpublished patients are described. Age at first presentation ranged from 1 to 34 years. The classical feature of macroaneurysms and vascular beading involving the retinal arteries was universal. Follow up extending up to 14 years after initial diagnosis revealed recurrent episodes of bleeding and leakage from macroaneurysms in 55% and 59% of patients, respectively. The majority of patients who underwent echocardiography (18/23) showed evidence of heart involvement, most characteristically pulmonary (valvular or supravalvular) stenosis, often requiring surgical correction (12/18). Four patients died in the course of the study from complications of pulmonary stenosis, cerebral hemorrhage, and cardiac complications. Liver involvement (usually cirrhosis) was observed in eight patients. Cerebral vascular involvement was observed in one patient, and stroke was observed in two. We conclude that RAMSVPS is a recognizable syndrome characterized by a high burden of ocular and systemic morbidity, and risk of premature death. Recommendations are proposed for early detection and management of these complications.

Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects.

Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix-loop-helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene. We report a 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. Chromosome analysis revealed a normal 46,XY karyotype, and a CHD sequencing panel was negative for pathogenic variants in NKX2.5, GATA4, TBX5, and CHD7. However, chromosomal microarray (CMA) testing identified a heterozygous 546.0-kb deletion on chromosome 4q34.1 (174364195_174910239[GRCh37/hg19]) that included exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot. The family history was also notable for a paternal uncle who had previously died from complications related to an unknown heart defect. Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD.

Use of magnetic resonance imaging combined with gene analysis for the diagnosis of fetal congenital heart disease.

BACKGROUND: Fetal deformity is a disease caused by abnormal chromosome structure, which may be influenced by genetic factors as well as the maternal and external environment. Magnetic resonance imaging (MRI) may be used to effectively diagnose fetus deformities. However it has been reported that gene analysis is a more accurate diagnostic method. The aim of the present study was to investigate the effectiveness of MRI in combination with gene analysis for the diagnosis of fetal congenital heart disease, a form of fetus deformity. METHODS: MRI, array comparative genome hybridization analysis and fluorescence in situ hybridization were used to analyze the effectiveness of the two methods in a total of 78 pregnant women with suspected fetal congenital heart disease. RESULTS: Our findings demonstrated that the combination of MRI and gene analysis resulted in significantly improved diagnostic accuracy, sensitivity and specificity for fetal congenital heart disease compared with either method alone. MRI combined with gene analysis confirmed 42 fetuses with pulmonary stenosis, 24 with aortic stenosis and 12 healthy fetuses, which was significantly improved compared with MRI or gene analysis alone. It was also observed that gene analysis was a more efficient method of diagnosis compared with MRI; however, the combination of the two methods was the most effective. CONCLUSION: In conclusion, the results of the present study suggest that MRI combined with gene analysis may be a more effective diagnostic method for fetal congenital heart disease compared with the current protocol.

Characterization of vitamin K-dependent carboxylase mutations that cause bleeding and nonbleeding disorders.

Vitamin K-dependent coagulation factors deficiency is a bleeding disorder mainly associated with mutations in γ-glutamyl carboxylase (GGCX) that often has fatal outcomes. Some patients with nonbleeding syndromes linked to GGCX mutations, however, show no coagulation abnormalities. The correlation between GGCX genotypes and their clinical phenotypes has been previously unknown. Here we report the identification and characterization of novel GGCX mutations in a patient with both severe cerebral bleeding disorder and comorbid Keutel syndrome, a nonbleeding malady caused by functional defects of matrix γ-carboxyglutamate protein (MGP). To characterize GGCX mutants in a cellular milieu, we established a cell-based assay by stably expressing 2 reporter proteins (a chimeric coagulation factor and MGP) in HEK293 cells. The endogenous GGCX gene in these cells was knocked out by CRISPR-Cas9-mediated genome editing. Our results show that, compared with wild-type GGCX, the patient's GGCX D153G mutant significantly decreased coagulation factor carboxylation and abolished MGP carboxylation at the physiological concentration of vitamin K. Higher vitamin K concentrations can restore up to 60% of coagulation factor carboxylation but do not ameliorate MGP carboxylation. These results are consistent with the clinical results obtained from the patient treated with vitamin K, suggesting that the D153G alteration in GGCX is the causative mutation for both the bleeding and nonbleeding disorders in our patient. These findings provide the first evidence of a GGCX mutation resulting in 2 distinct clinical phenotypes; the established cell-based assay provides a powerful tool for studying the clinical consequences of naturally occurring GGCX mutations in vivo.

22q11.2 Deletion Status and Perioperative Outcomes for Tetralogy of Fallot with Pulmonary Atresia and Multiple Aortopulmonary Collateral Vessels.

Deletion of 22q11.2 (del22q11) is associated with adverse outcomes in patients with tetralogy of Fallot (TOF). We sought to investigate its contribution to perioperative outcome in patients with a severe form of TOF characterized by pulmonary atresia (PA) or severe pulmonary stenosis (PS) and major aortopulmonary collateral arteries (MAPCAS). We conducted a retrospective review of patients with TOF/MAPCAS who underwent staged surgical reconstruction between 1995 and 2006. Groups were compared according to 22q11.2 deletion status using t-tests or the Wilcoxon Rank sum test. We included 26 subjects, 24 of whom survived the initial operation. Of those, 21 subjects had known deletion status and constitute the group for this analysis [15 with no deletion present (ND) and 6 del22q11 subjects]. There was no difference with respect to occurrence of palliative procedure prior to initial operation, or to timing of closure of the ventricular septal defect (VSD). Other than higher prevalence of prematurity (50%) in the del22q11 group versus no prematurity in the ND, the groups were comparable in terms of pre-operative characteristics. The intra- and post-operative course outcomes (length of cardiopulmonary bypass, use of vasopressors, duration of intensive care and length of hospital stay, tube-feeding) were also comparable. Although the del22q11 had longer mechanical ventilation than the ND, this difference was not significant [68 h (range 4-251) vs. 45 h (range 3-1005), p = 0.81]. In this detailed comparison of a small patient cohort, 22q11.2 deletion syndrome was not associated with adverse perioperative outcomes in patients with TOF, PA, and MAPCAS when compared to those without 22q11.2 deletion syndrome. These results are relevant to prenatal and neonatal pre-operative counseling and planning.

New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations.

We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty-five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene). Two of them (p.Gly392Glu in the BRAF gene and p.Gln164Lys in the MAP2K1 gene) were novel with a potentially pathogenic effect on the structure of these proteins. Statistically significant differences in the presence of pulmonary stenosis (63.64% vs. 23.81%, P = 0.013897) and cryptorchidism (76.47% vs. 30%, P = 0.040224) were identified as the result of comparison of the prevalence of phenotypic features in patients with the phenotype of Noonan syndrome and mutation in the PTPN11 gene, with the prevalence of the same features in patients without PTPN11 mutation. Cryptorchidism as a statistically significant feature in our patients with PTPN11 mutation was not reported as significant in other European countries (Germany, Italy and Greece). The majority of mutations were clustered in exons 3 (45.45%), 8 (22.73%), and 13 (22.73%) of the PTPN11 gene.

Coronary artery ectasia in Noonan syndrome: Report of an individual with SOS1 mutation and literature review.

Noonan syndrome (NS) is the second most frequent hereditary syndrome with cardiac involvement. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most prevalent cardiovascular abnormalities. We report on a 14-year-old girl with NS due to SOS1 mutation with pulmonary stenosis and idiopathic coronary ectasia. To the best of our knowledge, this is the first report describing coronary ectasia in a patient with NS secondary to a SOS1 mutation. We include a literature review of this rare association.

CLINICAL VARIABILITY IN TWO SISTERS WITH KEUTEL SYNDROME DUE TO A HOMOZYGOUS MUTATION IN MGP GENE.

Keutel syndrome (KS) is an autosomal recessive disease characterised by abnormal cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenosis, hearing loss and midface retrusion. KS is caused by homozygous mutations in MGP, a gene encoding Matrix Gla protein which acts as a calcification inhibitor in extracellular matrix. We present two Turkish sisters (22 and 13 years old) who had abnormal cartilage calcification, brachytelephalangism, congenital heart defect and chronic asthmatic bronchitis. The patients were homozygous for c.62-2A>G (IVS1-2 A>G) mutation in MGP gene. Abnormal cartilage calcification, brachytelephalangism and midfacial retrusion are the hallmarks of KS. It was observed that the younger sister had striking cartilaginous calcifications, midfacial retrusion and severe brachytelephalangism while her older sister had mild costal cartilaginous calcifications and brachytelephalangism without any midfacial retrusion. Intrafamiliar clinical variability for KS has not been described previously.

Keutel syndrome: report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis.

Keutel syndrome is a rare, autosomal recessive disorder characterized by diffuse cartilage calcification, peripheral pulmonary artery stenosis, midface retrusion, and short distal phalanges. To date, 28 patients from 18 families have been reported, and five mutations in the matrix Gla protein gene (MGP) have been identified. The matrix Gla protein (MGP) is a vitamin K-dependent extracellular protein that functions as a calcification inhibitor through incompletely understood mechanisms. We present the clinical manifestations of three affected siblings from a consanguineous Turkish family, in whom we detected the sixth MGP mutation (c.79G>T, which predicts p.E27X) and a fourth unrelated patient in whom we detected the seventh MGP mutation, a partial deletion of exon 4. Both mutations predict complete loss of MGP function. One of the patients presented initially with a working diagnosis of relapsing polychondritis. Clinical features suggestive of Keutel syndrome were also observed in one additional unrelated patient who was later found to have a deletion of arylsulfatase E, consistent with a diagnosis of X-linked recessive chondrodysplasia punctata. Through a discussion of these cases, we highlight the clinical overlap of Keutel syndrome, X-linked chondrodysplasia punctata, and the inflammatory disease relapsing polychondritis.

Long term follow-up of four patients with Keutel syndrome.

Keutel syndrome (KS) [OMIM 245150] is an autosomal recessive hereditary syndrome characterized by multiple peripheral pulmonary stenoses (PPS), brachytelephalangia, inner ear deafness, and abnormal cartilage ossification or calcification. Mutations in the matrix Gla protein (MGP) gene have been reported in different unrelated families with KS previously. MGP is an extracellular matrix protein and calcification inhibitor; mutations in its encoding gene result in cartilage ossification or calcification, the main presenting feature of KS. This report describes the findings of four sisters with KS born to consanguineous parents were followed for 26 years in an irregular fashion. During follow-up of the patients over the years the complications appear to be mostly involving the respiratory system. Permanent skin rashes, papillary microcarcinoma of the thyroid, asthma, massive bullous pulmonary emphysema, severe systemic arterial hypertension, and short term memory loss were observed during long term follow-up. The fertility status of the patients were also observed and infertility was observed in one of three married patients.

Genetics of valvular heart disease.

Valvular heart disease is associated with significant morbidity and mortality and often the result of congenital malformations. However, the prevalence is increasing in adults not only because of the growing aging population, but also because of improvements in the medical and surgical care of children with congenital heart valve defects. The success of the Human Genome Project and major advances in genetic technologies, in combination with our increased understanding of heart valve development, has led to the discovery of numerous genetic contributors to heart valve disease. These have been uncovered using a variety of approaches including the examination of familial valve disease and genome-wide association studies to investigate sporadic cases. This review will discuss these findings and their implications in the treatment of valvular heart disease.

Aberrant subclavian artery origin in tetralogy of Fallot with pulmonary stenosis is associated with chromosomal or genetic abnormality.

We determined the relationship between aortic arch anatomy in tetralogy of Fallot with pulmonary stenosis and chromosomal or genetic abnormality, by performing analysis of 257 consecutive patients undergoing surgical repair from January, 2003 to March, 2011. Chromosomal or genetic abnormality was identified in 49 of the 257 (19%) patients. These included trisomy 21 (n = 14); chromosome 22q11.2 deletion (n = 16); other chromosomal abnormalities (n = 9); CHARGE (n = 2); Pierre Robin (n = 2); and Kabuki, Alagille, Holt-Oram, Kaufman McKusick, Goldenhar, and PHACE (n = 1 each). Aortic anatomy was classified as left arch with normal branching, right arch with mirror image branching, left arch with aberrant right subclavian artery, or right arch with aberrant left subclavian artery. Associated syndromes occurred in 33 of 203 (16%) patients with left arch and normal branching (odds ratio 1); three of 36 (8%) patients with right arch and mirror image branching (odds ratio 0.4, 95% confidence interval 0.1-1.6); seven of eight (88%) patients with left arch and aberrant right subclavian artery (odds ratio 36, 95% confidence interval 4-302); and six of 10 (60%) patients with right arch and aberrant left subclavian artery (odds ratio 8, 95% confidence interval 2-26). Syndromes were present in 13 of 18 (72%) patients with either right or left aberrant subclavian artery (odds ratio 15, 95% confidence interval 4-45). Syndromes in patients with an aberrant subclavian artery included trisomy 21 (n = 4); chromosome 22q11.2 deletion (n = 5); and Holt-Oram, PHACE, CHARGE, and chromosome 18p deletion (n = 1 each). Aberrant right or left subclavian artery in tetralogy of Fallot with pulmonary stenosis is associated with an increased incidence of chromosomal or genetic abnormality, whereas right aortic arch with mirror image branching is not. The assessment of aortic arch anatomy at prenatal diagnosis can assist counselling.

Identification of Prostaglandin I2 Synthase Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis.

BACKGROUND: Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition. METHODS AND RESULTS: We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS. CONCLUSIONS: In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.

Congenital heart defects in oculodentodigital dysplasia: Report of two cases.

Oculodentodigital dysplasia is caused by mutations in the GJA1 gene. Oculodentodigital dysplasia presents with a spectrum of clinical features including craniofacial, ocular, dental, and limb anomalies. Although recent findings implicate the major role of GJA1 during cardiac organogenesis, congenital heart defects are infrequently reported in oculodentodigital dysplasia. Here we report on two patients with GJA1 mutations presenting with cardiac malformations and type III syndactyly. Patient 1 presented with pulmonary atresia, an intact septum, right ventricular hypoplasia and tricuspid stenosis. The infant had a small nose, thin columella and bilateral 4-5 syndactyly of the fingers. A de novo c.226C>T (p.Arg76Cys) mutation was identified. Patient 2 presented at 6 months with a ventricular septal defect. The child had hypoplastic alae nasi with a thin columella and bilateral 4-5 syndactyly of the digits. A de novo missense mutation, c.145C>G (p.Gln49Glu) was found. Our two patients underscore the importance of cardiac evaluations as part of the initial workup for patients with findings of oculodentodigital dysplasia. Conversely, those patients with type III syndactyly and congenital heart defect should be screened for GJA1 mutations.

The Genetics of Canine Pulmonary Valve Stenosis.

There have been recent advancements in understanding the genetic contribution to pulmonary valve stenosis (PS) in brachycephalic breeds such as the French Bulldog and Bulldog. The associated genes are transcriptions factors involved in cardiac development, which is comparable to the genes that cause PS in humans. However, validation studies and functional follow up is necessary before this information can be used for screening purposes.