Partial atrioventricular canal defect and aortic coarctation associated with variants in GDF1 and NOTCH1 genes: A case report.

BACKGROUND: A peculiar subgroup of patients with partial or complete atrioventricular canal defect exhibits a spectrum of left-sided obstructions including right ventricular dominance and aortic coarctation. The association of atrioventricular canal defect with left-sided obstructions is found in several genetic syndromes; however, the molecular basis of nonsyndromic atrioventricular canal defect with aortic coarctation is still poorly understood. Although some candidate genes for nonsyndromic atrioventricular canal defect are known, a complex oligogenic inheritance determined in some cases by the co-occurrence of multiple variants has also been hypothesized. CASE REPORT: We describe a nonsyndromic infant with mesocardia with viscero-atrial situs solitus, partial atrioventricular canal defect, mild right ventricular dominance, and coarctation of the aorta. Next generation sequencing genetic testing revealed variants in two genes, GDF1 and NOTCH1, previously reported in association with atrioventricular canal defect and left-sided obstructive lesions, respectively. CONCLUSION: The present report could support the hypothesis that the co-occurrence of cumulative variants may be considered as genetic predisposing risk factor for specific congenital heart defects.

Dihydropyrimidinase deficiency with atrioventricular septal defect: a case report.

OBJECTIVES: Dihydropyrimidinase deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway, with fewer than 40 patients published. Clinical findings are variable and some patients may remain asymptomatic. Global developmental delay and increased susceptibility to 5-fluorouracil are commonly reported. Here we present atrioventricular septal defect as a novel feature in dihydropyrimidinase deficiency. CASE PRESENTATION: A four-year-old male with global developmental delay, dysmorphic facies, autistic features and a history of seizures was diagnosed with dihydropyrimidinase deficiency based on strikingly elevated urinary dihydrouracil and dihydrothymine and a homozygous pathogenic nonsense variant in DPYS gene. He had a history of complete atrioventricular septal defect corrected surgically in infancy. CONCLUSIONS: This is the second report of congenital heart disease in dihydropyrimidinase deficiency, following a single patient with a ventricular septal defect. The rarity of the disease and the variability of the reported findings make it difficult to describe a disease-specific clinical phenotype. The mechanism of neurological and other systemic findings is unclear. Dihydropyrimidinase deficiency should be considered in patients with microcephaly, developmental delay, epilepsy and autistic traits. We suggest that congenital heart disease may also be a rare phenotypic feature.

Molecular Pathways and Animal Models of Atrioventricular Septal Defect.

The development of a fully functional four-chambered heart is critically dependent on the correct formation of the structures that separate the atrial and ventricular chambers. Perturbation of this process typically results in defects that allow mixing of oxygenated and deoxygenated blood. Atrioventricular septal defects (AVSD) form a class of congenital heart malformations that are characterized by the presence of a primary atrial septal defect (pASD), a common atrioventricular valve (cAVV), and frequently also a ventricular septal defect (VSD). While AVSD were historically considered to result from failure of the endocardial atrioventricular cushions to properly develop and fuse, more recent studies have determined that inhibition of the development of other components of the atrioventricular mesenchymal complex can lead to AVSDs as well. The role of the dorsal mesenchymal protrusion (DMP) in AVSD pathogenesis has been well-documented in studies using animal models for AVSDs, and in addition, preliminary data suggest that the mesenchymal cap situated on the leading edge of the primary atrial septum may be involved in certain situations as well. In this chapter, we review what is currently known about the molecular mechanisms and animal models that are associated with the pathogenesis of AVSD.

Human Genetics of Atrioventricular Septal Defect.

Atrioventricular septal defects (AVSD), also known as a common atrioventricular canal (CAVC), are clinically severe heart malformations that affect about 1 out of every 2100 live births. AVSD makes up about 5% of all congenital heart defects. AVSD is associated with cytogenetic disorders such as Down syndrome and numerous other rare genetic syndromes, but also occurs as a simplex trait. Studies in mouse models have identified over 100 genetic mutations that have the potential to cause an AVSD. However, studies in humans indicate that AVSD is genetically heterogeneous, and that the cause in humans is very rarely a single-gene defect. Familial cases do occur albeit rarely, usually with autosomal dominant inheritance and variable expression. In addition, the frequent occurrence of AVSD in some syndromes with known genetic causes such as heterotaxy syndrome points to additional genes/pathways that increase AVSD risk. Accordingly, while the genetic underpinnings for most AVSD remain unknown, there have been advances in identifying genetic risk factors for AVSD in both syndromic and nonsyndromic cases. This chapter summarizes the current knowledge of the genetic basis for AVSD.

Revisiting Atrioventricular Septal Defects: Exploring Chromosomal Abnormalities, Cardiac and Extracardiac Anomalies in a Contemporary Prenatal Cohort.

To estimate if there is an association between partial AVSD with chromosomal abnormalities, cardiac and extracardiac malformations, and to report the outcomes of prenatally diagnosed AVSD in a large, contemporary cohort. This is a retrospective cohort study of 190 prenatally diagnosed fetal AVSD between 2014 and 2023. Type of AVSD (complete vs partial), additional cardiac findings, extracardiac findings, presence of a heterotaxy, results of prenatal karyotype, and pregnancy outcomes were documented and analyzed. A total of 190 cases of fetal AVSD were analyzed. Complete AVSDs comprised 141 (74.2%) of the cohort, while partial AVSDs comprised 49 (25.7%). Karyotype was completed in 131 cases, and in 98 (74.8%) cases chromosomal abnormalities were identified, with trisomy 21 being the most common (53/131, 40.5%). Complete AVSDs were associated with trisomy 21 (45.5%, p = 0.04), Isolated cases of complete AVSDs (p = 0.03). Partial AVSDs were associated with trisomy 18 (53.1%, p < 0.001). In cases of partial AVSDs with aneuploidies, 7 (70%) had an ostium primum defect and 20 (90.9%) of AV canal type VSD. Isolated partial AVSD had no clear association with aneuploidies. There were additional cardiac anomalies in 96 (50.5%) and extracardiac anomalies in 134 (70.5%) of the cohort. There were no differences between partial and complete AVSD in rate of additional cardiac and extracardiac anomalies. AVSD was part of a heterotaxy in 47 (24.7%) of cases, and heterotaxy was associated with complete AVSD in the majority of cases (43/47, 91.4%, p = 0.003). Fetal partial AVSDs are associated with trisomy 18. Fetal complete AVSDs, even isolated, are associated with trisomy 21. There were no differences in association of other aneuploidies, additional cardiac findings, or extracardiac anomalies between prenatally diagnosed complete AVSDs and partial AVSDs.

Oculo-facio-cardio-dental (OFCD) syndrome: a case report.

BACKGROUND: Oculo-facio-cardio-dental (OFCD) syndrome is a rare condition that affects the eyes, face, heart, and teeth of patients. One notable dental characteristic of OFCD is radiculomegaly, or root gigantism, which highlights the role of dentists in detecting this syndrome. OFCD is an X-linked dominant syndrome that results from a variant in the BCOR gene. Our study presents the first documented case of OFCD in Vietnam and reports a novel BCOR gene variant observed in this case. CASE PRESENTATION: A 19-year-old Vietnamese female patient with an extremely long root with an abscess was clinically examined for the expression of OFCDs. The radiograph and the variant in BCOR gene were also evaluated. We identified abnormalities in the teeth, as well as ocular, facial, and cardiac features, with radiculomegaly of the canines being a specific symptom for OFCDs. The patient's genetic analysis revealed a pathogenic heterozygous deletion at intron 11 of the BCOR gene, representing a novel variant. CONCLUSION: Oculo-facio-cardio-dental syndrome (OFCD) is an extremely rare condition characterized by abnormalities in the eyes, face, heart, and teeth, often caused by variants in the BCOR gene. Radiculomegaly, or enlarged dental roots, is a key diagnostic feature of OFCD, and early detection is crucial for preventing future dental complications.

Contribution of LRP1 in Human Congenital Heart Disease Correlates with Its Roles in the Outflow Tract and Atrioventricular Cushion Development.

Due to the prevalence of congenital heart disease in the human population, determining the role of variants in congenital heart disease (CHD) can give a better understanding of the cause of the disorder. A homozygous missense mutation in the LDL receptor-related protein 1 (Lrp1) in mice was shown to cause congenital heart defects, including atrioventricular septal defect (AVSD) and double outlet right ventricle (DORV). Integrative analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets and spatial transcriptomics of human and mouse hearts indicated that LRP1 is predominantly expressed in mesenchymal cells and mainly located in the developing outflow tract and atrioventricular cushion. Gene burden analysis of 1922 CHD individuals versus 2602 controls with whole-exome sequencing showed a significant excess of rare damaging LRP1 mutations in CHD (odds ratio (OR) = 2.22, p = 1.92 × 10-4), especially in conotruncal defect with OR of 2.37 (p = 1.77 × 10-3) and atrioventricular septal defect with OR of 3.14 (p = 0.0194). Interestingly, there is a significant relationship between those variants that have an allele frequency below 0.01% and atrioventricular septal defect, which is the phenotype observed previously in a homozygous N-ethyl-N-nitrosourea (ENU)-induced Lrp1 mutant mouse line.

X-linked BCOR variants identified in Chinese Han patients with congenital heart disease.

BACKGROUND: Congenital heart disease (CHD) frequently manifests as a complex phenotype and approximately one-third of cases may be caused by genetic factors. BCOR, an X-linked gene encoding the corepressor of BCL6, has been demonstrated to be closely involved in human heart development. However, whether BCOR variants represent the genetic etiology underlying CHD needs further investigation. METHODS: We performed whole exome sequencing on CHD nuclear families and identified a candidate gene, BCOR, by robust bioinformatic analysis and medical literature searches. Targeted DNA sequencing of the candidate gene was conducted and then the association between variants and the risk of developing CHD was analyzed. The effects of BCOR mutations on gene expression, localization, protein interaction, and signaling pathways were evaluated in vitro. RESULTS: We identified a BCOR hemizygous missense variant (c.1448C>T, p.Pro483Leu) in a male proband presented with CHD/heterotaxy. Sanger sequencing confirmed that this variant was inherited from his asymptomatic mother. Interestingly, through literature searches, we observed another novel BCOR hemizygous missense variant (c.1619G>A, p.Arg540Gln) in a CHD patient with heterotaxy, supporting the pathogenic evidence of BCOR variants. Functional experiments conducted in vitro revealed that the variant p.Pro483Leu altered the subcellular localization of BCOR protein, disrupted its interaction with BCL6, and significantly promoted cell proliferation, whereas the variant p.Arg540Gln displayed no obvious effects. Nevertheless, transcriptional analysis revealed that down-regulation of BCOR substantially enhanced the activities of mitogen-activated protein and phosphoinositide 3-kinase-AKT signaling pathways, which are closely attributed to heart development. Targeted sequencing of 932 sporadic CHD patients enriched nine variants of BCOR predicted as likely rare and damaging and a septal defect was present in 81.8% (9/11) of them, including the two probands, which was consistent with the possible phenotype caused by BCOR defects. CONCLUSIONS: The findings of the present study indicate that variants in BCOR may predispose individuals to CHD in the Chinese Han population.

High-risk genes involved in common septal defects of congenital heart disease.

The septation defect is one of the main categories of congenital heart disease (CHD). They can affect the septation of the atria leading to atrial septal defect (ASD), septation of ventricles leading to ventricular septal defect (VSD), and formation of the central part of the heart leading to atrioventricular septal defect (AVSD). Disruption of critical genetic factors involved in the proper development of the heart structure leads to CHD manifestation. Because of this, to identify the high-risk genes involved in common septal defects, a comprehensive search of the literature with the help of databases and the WebGestalt analysis tool was performed. The high-risk genes identified in the analysis were checked in 16 Indian whole-exome sequenced samples, including 13 VSD and three Tetralogy of Fallot for in silico validation. This data revealed three variations in GATA4, i.e., c.C1223A at exon 6: c.C602A and c.C1220A at exon 7; and one variation in MYH6, i.e., c.G3883C at exon 28 in two VSD cases. This study supports previously published studies that suggested GATA4 and MYH6 as the high-risk genes responsible for septal defects. Thus, this study contributes to a better understanding of the genes involved in heart development by identifying the high-risk genes and interacting proteins in the pathway.

Predisposition to atrioventricular septal defects may be caused by SOX7 variants that impair interaction with GATA4.

Atrioventricular septal defects (AVSD) are a complicated subtype of congenital heart defects for which the genetic basis is poorly understood. Many studies have demonstrated that the transcription factor SOX7 plays a pivotal role in cardiovascular development. However, whether SOX7 single nucleotide variants are involved in AVSD pathogenesis is unclear. To explore the potential pathogenic role of SOX7 variants, we recruited a total of 100 sporadic non-syndromic AVSD Chinese Han patients and screened SOX7 variants in the patient cohort by targeted sequencing. Functional assays were performed to evaluate pathogenicity of nonsynonymous variants of SOX7. We identified three rare SOX7 variants, c.40C > G, c.542G > A, and c.743C > T, in the patient cohort, all of which were found to be highly conserved in mammals. Compared to the wild type, these SOX7 variants had increased mRNA expression and decreased protein expression. In developing hearts, SOX7 and GATA4 were highly expressed in the region of atrioventricular cushions. Moreover, SOX7 overexpression promoted the expression of GATA4 in human umbilical vein endothelial cells. A chromatin immunoprecipitation assay revealed that SOX7 could directly bind to the GATA4 promoter and luciferase assays demonstrated that SOX7 activated the GATA4 promoter. The SOX7 variants had impaired transcriptional activity relative to wild-type SOX7. Furthermore, the SOX7 variants altered the ability of GATA4 to regulate its target genes. In conclusion, our findings showed that deleterious SOX7 variants potentially contribute to human AVSD by impairing its interaction with GATA4. This study provides novel insights into the etiology of AVSD and contributes new strategies to the prenatal diagnosis of AVSD.

Antenatal presentation and supratentorial brain abnormalities in a child with Poretti-Boltshauser syndrome.

Autosomal recessively inherited Poretti-Boltshauser syndrome (PBS) with loss-of-function variants in the LAMA1 gene are characterized by motor and speech developmental delay, high myopia, and cerebellar dysplasia with cysts without any supratentorial abnormalities on neuroimaging. There is no muscular involvement. We report an eight months child with genetically confirmed PBS who presented with antenatally detected ventriculomegaly and had global developmental delay, focal seizures, myopic degeneration of fundi. Neuroimaging showed asymmetric ventriculomegaly and lissencephaly in bilateral temporal horns along with cerebellar dysplasia and cysts. These supratentorial abnormalities and antenatal presentation as ventriculomegaly have not been reported earlier. Child also had a small subaortic ventricular septal defect.

Copy number variation analysis in Chinese children with complete atrioventricular canal and single ventricle.

BACKGROUND: Congenital heart disease (CHD) is one of the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here we screened genome-wide CNVs in Chinese children with complete atrioventricular canal (CAVC) and single ventricle (SV), since there were scarce researches dedicated to these two types of CHD. METHODS: We screened CNVs in 262 sporadic CAVC cases and 259 sporadic SV cases respectively, using a customized SNP array. The detected CNVs were annotated and filtered using available databases. RESULTS: Among 262 CAVC patients, we identified 6 potentially-causative CNVs in 43 individuals (16.41%, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 90.70% CAVC patients with detected CNVs (39/43) were found to carry duplications of 21q11.2-21q22.3, which were recognized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1.0 (24:15), and the rate of pulmonary hypertension (PH) was 41.03% (16/39). Additionally, 6 potentially-causative CNVs were identified in the SV patients (2.32%, 6/259), and none of them was trisomy 21. Most CNVs identified in our cohort were classified as rare (< 1%), occurring just once among CAVC or SV individuals except the 21q11.2-21q22.3 duplication (14.89%) in CAVC cohort. CONCLUSIONS: Our study identified 12 potentially-causative CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and high incidence of PH. The presence of potentially-causative CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost.

In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5+/- mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes raise or lower the risk of specific defects via pairwise (G×GNkx) and higher-order (G×G×GNkx) interactions with Nkx2-5. Their effect sizes correlate with the severity of a defect. The risk loci for mild, atrial septal defects exert predominantly small G×GNkx effects, while the loci for severe, atrioventricular septal defects exert large G×GNkx and G×G×GNkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G×G×GNkx effects are three times more likely to suppress risk when the genotypes at the first two loci are from the same rather than different parental inbred strains. This suggests the genetic coadaptation of interacting G×G×GNkx loci, a phenomenon that Dobzhansky first described in Drosophila. Thus, epistasis plays dual roles in the pathogenesis of congenital heart disease and the robustness of cardiac development. The empirical results suggest a relationship between the fitness cost and genetic architecture of a disease phenotype and a means for phenotypic robustness to have evolved.

Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region.

The atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-ß, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.

The first post-natal clinical description of true mosaic complete tetrasomy 21: A case report.

Tetrasomy 21 is a rare occurrence. Only 14 cases have been reported in the literature, 8 of which are partial tetrasomy cases and 6 which are complete tetrasomy cases. Of the incidences, no proband with true complete tetrasomy 21 has survived the neonatal period. We report complete mosaic tetrasomy 21 in a female infant with the typical Down syndrome phenotype, including Hirschsprung's disease and atrioventricular (AV) canal defect. This is in contrast to cases of partial tetrasomy 21, which often have an atypical trisomy 21 presentation and multiple nonspecific traits, including short stature, microcephaly, and developmental delays. This case demonstrates the difference in clinical presentation between the partial and complete subtype of tetrasomy 21 and provides the first postnatal clinical picture of an infant with true mosaic complete tetrasomy 21.

Discordant congenital heart defects in monochorionic twins: Risk factors and proposed pathophysiology.

A six-fold increase in congenital heart defects (CHD) exists among monochorionic (MC) twins compared to singleton or dichorionic twin pregnancies. Though MC twins share an identical genotype, discordant phenotypes related to CHD and other malformations have been described, with reported rates of concordance for various congenital anomalies at less than 20%. Our objective was to characterize the frequency and spectrum of CHD in a contemporary cohort of MC twins, coupled with genetic and clinical variables to provide insight into risk factors and pathophysiology of discordant CHD in MC twins. Retrospective analysis of all twins receiving prenatal fetal echocardiography at a single institution from January 2010 -March 2020 (N = 163) yielded 23 MC twin pairs (46 neonates) with CHD (n = 5 concordant CHD, n = 18 discordant CHD). The most common lesions were septal defects (60% and 45.5% in concordant and discordant cohorts, respectively) and right heart lesions (40% and 18.2% in concordant and discordant cohorts, respectively). Diagnostic genetic testing was abnormal for 20% of the concordant and 5.6% of the discordant pairs, with no difference in rate of abnormal genetic results between the groups (p = 0.395). No significant association was found between clinical risk factors and development of discordant CHD (p>0.05). This data demonstrates the possibility of environmental and epigenetic influences versus genotypic factors in the development of discordant CHD in monochorionic twins.

Setd5 is required in cardiopharyngeal mesoderm for heart development and its haploinsufficiency is associated with outflow tract defects in mouse.

Congenital heart defects are a feature of several genetic haploinsufficiency syndromes, often involving transcriptional regulators. One property of haploinsufficient genes is their propensity for network interactions at the gene or protein level. In this article we took advantage of an online dataset of high throughput screening of mutations that are embryonic lethal in mice. Our aim was to identify new genes where the loss of function caused cardiovascular phenotypes resembling the 22q11.2 deletion syndrome models, that is, heterozygous and homozygous loss of Tbx1. One gene with a potentially haploinsufficient phenotype was identified, Setd5, thought to be involved in chromatin modification. We found murine Setd5 haploinsufficiency to be associated with double outlet right ventricle and perimembranous ventricular septal defect, although no genetic interaction with Tbx1 was detected. Conditional mutagenesis revealed that Setd5 was required in cardiopharyngeal mesoderm for progression of the heart tube through the ballooning stage to create a four-chambered heart.

Kallmann syndrome in a patient with Weiss-Kruszka syndrome and a de novo deletion in 9q31.2.

Patients with deletions on chromosome 9q31.2 may exhibit delayed puberty, craniofacial phenotype including cleft lip/palate, and olfactory bulb hypoplasia. We report a patient with congenital HH with anosmia (Kallmann syndrome, KS) and a de novo 2.38 Mb heterozygous deletion in 9q31.2. The deletion breakpoints (determined with whole-genome linked-read sequencing) were in the FKTN gene (9:108,331,353) and in a non-coding area (9:110,707,332) (hg19). The deletion encompassed six protein-coding genes (FKTN, ZNF462, TAL2, TMEM38B, RAD23B, and KLF4). ZNF462 haploinsufficiency was consistent with the patient's Weiss-Kruszka syndrome (craniofacial phenotype, developmental delay, and sensorineural hearing loss), but did not explain his KS. In further analyses, he did not carry rare sequence variants in 32 known KS genes in whole-exome sequencing and displayed no aberrant splicing of 15 KS genes that were expressed in peripheral blood leukocyte transcriptome. The deletion was 1.8 Mb upstream of a KS candidate gene locus (PALM2AKAP2) but did not suppress its expression. In conclusion, this is the first report of a patient with Weiss-Kruszka syndrome and KS. We suggest that patients carrying a microdeletion in 9q31.2 should be evaluated for the presence of KS and KS-related features.

The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling.

Cardiac septum malformations account for the largest proportion in congenital heart defects. The transcription factor Sox7 has critical functions in the vascular development and angiogenesis. It is unclear whether Sox7 also contributes to cardiac septation development. We identified a de novo 8p23.1 deletion with Sox7 haploinsufficiency in an atrioventricular septal defect (AVSD) patient using whole exome sequencing in 100 AVSD patients. Then, multiple Sox7 conditional loss-of-function mice models were generated to explore the role of Sox7 in atrioventricular cushion development. Sox7 deficiency mice embryos exhibited partial AVSD and impaired endothelial to mesenchymal transition (EndMT). Transcriptome analysis revealed BMP signaling pathway was significantly downregulated in Sox7 deficiency atrioventricular cushions. Mechanistically, Sox7 deficiency reduced the expressions of Bmp2 in atrioventricular canal myocardium and Wnt4 in endocardium, and Sox7 binds to Wnt4 and Bmp2 directly. Furthermore, WNT4 or BMP2 protein could partially rescue the impaired EndMT process caused by Sox7 deficiency, and inhibition of BMP2 by Noggin could attenuate the effect of WNT4 protein. In summary, our findings identify Sox7 as a novel AVSD pathogenic candidate gene, and it can regulate the EndMT involved in atrioventricular cushion morphogenesis through Wnt4-Bmp2 signaling. This study contributes new strategies to the diagnosis and treatment of congenital heart defects.

Whole-exome sequencing identified a novel homozygous ASPH frameshift variant causing Traboulsi syndrome in a Chinese family.

BACKGROUND: Traboulsi syndrome is a rare disorder characterized by ectopia lentis and facial dysmorphism (large beaked nose), which was only reported in 18 individuals to date. It is caused by homozygous/compound heterozygous variants in the aspartate/asparagine-ß-hydroxylase (ASPH) gene, which hydroxylates the aspartic acid and asparagine in epidermal growth factor-like domains of various proteins. METHODS: Whole-exome and Sanger sequencing were used to identify the disease-causing gene of the patient in a consanguineous Chinese family. Domain analysis was applied to predict the impact of the variant on ASPH protein. RESULTS: Through exome and Sanger sequencing, we identified a novel homozygous ASPH variant (NM_004318.4:c.1910del/NP_004309.2: p.(Asn637MetfsTer15)) in the patient, which may lead to blockage of the ASPH function through truncating the AspH oxygenase domain of the ASPH protein and/or nonsense-mediated decay of the ASPH transcript. This is the first report of Traboulsi syndrome in a Chinese patient who was combined with ventricular septal defect, lung bullae, and recurrent spontaneous pneumothorax. CONCLUSION: Our results revealed the clinical characteristics of the first Chinese patient with Traboulsi syndrome. Additionally, our study expands the mutational spectrum of Traboulsi syndrome and provides information for clinical genetic counseling to this family.