Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1.

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva and operative tissue, when available, were collected. Among the 102 children, 13 were having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection, and RNA-Seq analysis of NF1, MAPK pathway genes and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation and increased MCP1 expression. In summary, NF-1-related RVH in children is rare but often severe and progressive and, as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants.

Patent ductus arteriosus (PDA) and coarctation of the aorta (CoA) are relatively common congenital heart defects. Pathogenic variants in PRDM6, which encodes a smooth-muscle-cell-specific transcription factor, have now been etiologically associated with non-syndromic PDA. We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant.

PHACES-like syndrome with TMEM260 compound heterozygous variants.

PHACES syndrome is a multiple congenital disorder with unknown etiology that is characterized by Posterior fossa anomalies, Hemangioma, Arterial lesions, Cardiac abnormalities/coarctation of the aorta, Eye anomalies, and Sternal cleft. Compound heterozygous or homozygous TMEM260 variants cause structural heart defects and renal anomalies syndrome (SHDRA). We describe a 10-year-old male patient with a PHACES-like syndrome and TMEM260 compound heterozygous variants who demonstrated overlapping phenotypes between the two syndromes. He presented with truncus arteriosus, supraumbilical raphe, ophthalmological abnormality, vertebral abnormality, borderline intellectual disability, and hearing loss. He had normal serum creatinine. In proband exome sequencing, compound heterozygous TMEM260 variants (NM_017799.4 c.1617delG p.(Trp539Cysfs*9)/c.1858C > T p.(Gln620*)) were identified. Twelve patients have been reported with TMEM260-related SHDRA: 10 had truncus arteriosus and 6 had renal failure. One previously reported patient had facial port wine nevus and another patient had supraumbilical raphe, which are the cardinal signs for PHACES syndrome. TMEM260-related SHDRA could share overlapping clinical features with PHACES syndrome. This report expands the phenotypic spectrum of a TMEM260-related disorder.

Renin Cell Baroreceptor, a Nuclear Mechanotransducer Central for Homeostasis.

[Figure: see text].

RNA sequencing analyses in infants patients with coarctation of the aorta.

BACKGROUND: Coarctation of the aorta (CoA) is a serious innate heart disease. Although surgery results are generally good, some complications such as recoarctation and aortic aneurysm or persistent hypertension were serious threats to patient's health. To better understand the pathology of CoA and its underlying molecular mechanism is particularly important for early diagnosis and preventing the occurrence of its complications. However, the mechanisms of CoA remain unclear, especially for infants. METHODS: RNA sequencing (RNA-seq) was used to identify the differentially expressed genes (DEGs) in vascular tissues of 12 patients with CoA and 10 normal participants form 3- to 34-month-old infants. The characteristic of DEGs were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunochemical staining (IHC) in vessels of patients with CoA and normal infants. RESULTS: A total of 2491 DEGs with the false discovery rate less than 0.05(> 1.5-fold, P < 0.05 change) were identified, including 443 upregulated genes and 2048 downregulated genes. The Gene Ontology enrichment analysis showed that 26 out of the 2491 DEGs identified were associated with cardiovascular diseases. These 26 genes were mainly associated with extracellular matrix (ECM) and smooth muscle cells (SMCs) differentiation. Three DEGs, that is, CNN1 (calponin), α-actinin1 and myosin heavy chain 11 MYH11, were validated using qRT-PCR and Western blot analysis. In addition, immunochemical staining showed that calponin and MYH11 were highly expressed on the surface and in the deep layers of the thickened intima respectively. CONCLUSION: This study comprehensively characterized the CoA transcriptome. Migration of extracellular matrix (ECM) and smooth muscle cells (SMCs) to the subendothelial space may be the major characteristic of CoA in infants.

Right arch with prostaglandin-dependent coarctation and aberrant left carotid artery in a 22q11.2 deletion infant.

Right aortic arch in association with coarctation of the aorta and vascular ring is a rare anatomy. We present an infant with chromosome 22q11.2 deletion, who had the right aortic arch with retroesophageal aberrant left subclavian artery and left internal carotid artery. The left external carotid artery and right common carotid artery originated together from the ascending aorta as a bovine branch. The infant also had severe coarctation, which was prostaglandin dependent.

Blood pressure changes PVAT function and transcriptome: use of the mid-thoracic aorta coarcted rat.

Perivascular adipose tissue (PVAT) modifies the contractile function of the vessel it surrounds (outside-in signaling). Little work points to the vessel actively affecting its surrounding PVAT. We hypothesized that inside-out arterial signaling to PVAT would be evidenced by the response of PVAT to changes in tangential vascular wall stress. Rats coarcted in the mid-thoracic aorta created PVAT tissues that would exemplify pressure-dependent changes (above vs. below coarctation); a sham rat was used as a control. Radiotelemetry revealed a ∼20 mmHg systolic pressure gradient across the coarctation 4 wk after surgery. Four measures (histochemical, adipocyte progenitor proliferation and differentiation, isometric tone, and bulk mRNA sequencing) were used to compare PVAT above versus below the ligature in sham and coarcted rats. Neither aortic collagen deposition in PVAT nor arterial media/radius ratio above coarctation was increased versus below segments. However, differentiated adipocytes derived from PVAT above the coarctation accumulated substantially less triglycerides versus those below; their relative proliferation rate as adipogenic precursors was not different. Functionally, the ability of PVAT to assist stress relaxation of isolated aorta was reduced in rings above versus below the coarctation. Transcriptomic analyses revealed that the coarctation resulted in more differentially expressed genes (DEGs) between PVAT above versus below when compared with sham samples from the same locations. A majority of DEGs were in PVAT below the coarctation and were enriched in neuronal/synaptic terms. These findings provide initial evidence that signaling from the vascular wall, as stimulated by a pressure change, influences the function and transcriptional profile of its PVAT.NEW & NOTEWORTHY A mid-thoracic aorta coarcted rat was created to generate a stable pressure difference above versus below the coarctation ligature. This study determined that the PVAT around the thoracic aorta exposed to a higher pressure has a significantly reduced ability to assist stress relaxation versus that below the ligature and appears to retain the ability to be anticontractile. At the same time, the PVAT around the thoracic aorta exposed to higher pressure had a reduced adipogenic potential versus that below the ligature. Transcriptomics analyses indicated that PVAT below the coarctation showed the greatest number of DEGs with an increased profile of the synaptic neurotransmitter gene network.

Small Supernumerary Ring Chromosome Derived from an Inverted Duplication of 13q11.2q14 in a Fetus with Coarctation of the Aorta.

Here, we report a molecular characterization of a small supernumerary marker chromosome (sSMC) derived from the most proximal region of 13q present in a fetus with coarctation of the aorta at ultrasound examination during prenatal diagnosis. Cultured umbilical cord blood cells showed a de novo extra ring-shaped sSMC in 76% of the cells using a standard banding technique. SNP array revealed a tetrasomy of about 28.4 Mb in the long arm of chromosome 13 from band 13q11 to 13q14.11 in the fetus's cells. Metaphase/interphase FISH using specific probes located at 13q11, 13q12.11, and 13q14.11, respectively, demonstrated that the supernumerary ring chromosome was derived from an inverted duplication of the region 13q11q14.11 with a conventional centromere. To the best of our knowledge, this is the first time that an inverted duplication of the most proximal region 13q11q14.11 in a ring chromosome is characterized. The findings we presented here deepen our understanding of the clinical consequences of tetrasomy in this region and may be of help for further studies of critical regions in chromosome 13.

Moyamoya angiopathy in PHACE syndrome not associated with RNF213 variants.

Moyamoya angiopathy is a rare vasculopathy with stenosis and/or occlusion of bilateral intracranial parts of internal carotid arteries and/or proximal parts of middle and anterior cerebral arteries. PHACE syndrome is characterized by large segmental hemangiomas in the cervical-facial region. Both conditions are known to be associated in rare cases. Recently, it was discussed in the literature that RNF213 variants could be etiologically involved in this association. Here, we describe a childhood case with this rare co-occurrence in which we did not identify any rare RNF213 variant. The clinical and genetic backgrounds are discussed.

A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta.

Aims: Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and confers substantial morbidity despite treatment. It is increasingly recognized as a highly heritable condition. The aim of the study was to search for sequence variants that affect the risk of CoA. Methods and results: We performed a genome-wide association study of CoA among Icelanders (120 cases and 355 166 controls) based on imputed variants identified through whole-genome sequencing. We found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp in MYH6 (odds ratio = 44.2, P = 5.0 × 10-22), encoding the alpha-heavy chain subunit of cardiac myosin, an essential sarcomere protein. Approximately 20% of individuals with CoA in Iceland carry this mutation. We show that p.Arg721Trp also associates with other CHDs, in particular bicuspid aortic valve. We have previously reported broad effects of p.Arg721Trp on cardiac electrical function and strong association with sick sinus syndrome and atrial fibrillation. Conclusion: Through a population approach, we found that a rare missense mutation p.Arg721Trp in the sarcomere gene MYH6 has a strong effect on the risk of CoA and explains a substantial fraction of the Icelanders with CoA. This is the first mutation associated with non-familial or sporadic form of CoA at a population level. The p.Arg721Trp in MYH6 causes a cardiac syndrome with highly variable expressivity and emphasizes the importance of sarcomere integrity for cardiac development and function.

Left-sided congenital heart lesions in mosaic Turner syndrome.

In the era of the diseasomes and interactome networks, linking genetics with phenotypic traits in Turner syndrome should be studied thoroughly. As a part of this stratagem, mosaicism of both X and Y chromosome which is a common finding in TS and an evaluation of congenital heart diseases in the different situations of mosaic TS types, can be helpful in the identification of disturbed sex chromosomes, genes and signaling pathway actors. Here we report the case of a mosaic TS associated to four left-sided CHD, including BAV, COA, aortic aneurysms and dissections at an early age. The mosaicism included two cell lines, well-defined at the cytogenetic and molecular levels: a cell line which is monosomic for Xp and Xq genes (45,X) and another which is trisomic for pseudoautosomal genes that are present on the X and Y chromosomes and escape X inactivation: 45,X[8]/46,X,idic(Y)(pter→q11.2::q11.2→pter)[42]. This case generates two hypotheses about the contribution of genes linked to the sex chromosomes and the signaling pathways involving these genes, in left-sided heart diseases. The first hypothesis suggests the interaction between X chromosome and autosomal genes or loci of aortic development, possibly dose-dependent, and which could be in the framework of TGF-ß-SMAD signaling pathways. The second implies that left-sided congenital heart lesions involve sex chromosomes loci. The reduced dosage of X chromosome gene(s), escaping X inactivation during development, contributes to this type of CHD. Regarding our case, these X chromosome genes may have homologues at the Y chromosome, but the process of inactivation of the centromeres of the isodicentric Y spreads to the concerned Y chromosome genes. Therefore, this case emerges as an invitation to consider the mosaics of Turner syndrome and to study their phenotypes in correlation with their genotypes to discover the underlying developmental and genetic mechanisms, especially the ones related to sex chromosomes.

Spontaneous regression of severe aortic coarctation in trisomy 18.

Spontaneous regression of severe aortic coarctation with ductus dependency has not been reported. We experienced a case of trisomy 18 with spontaneous regression of severe aortic coarctation complicated by ventricular septal defect and patent ductus arteriosus. The aortic isthmus diameter was 1.2 mm at birth. After 5 months, it increased to 4.5 mm, and the shape of the isthmus was fully normalised.

MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus.

Cardiac left ventricular outflow tract (LVOT) defects represent a common but heterogeneous subset of congenital heart disease for which gene identification has been difficult. We describe a 46,XY,t(1;5)(p36.11;q31.2)dn translocation carrier with pervasive developmental delay who also exhibited LVOT defects, including bicuspid aortic valve (BAV), coarctation of the aorta (CoA) and patent ductus arteriosus (PDA). The 1p breakpoint disrupts the 5' UTR of AHDC1, which encodes AT-hook DNA-binding motif containing-1 protein, and AHDC1-truncating mutations have recently been described in a syndrome that includes developmental delay, but not congenital heart disease [Xia, F., Bainbridge, M.N., Tan, T.Y., Wangler, M.F., Scheuerle, A.E., Zackai, E.H., Harr, M.H., Sutton, V.R., Nalam, R.L., Zhu, W. et al. (2014) De Novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am. J. Hum. Genet., 94, 784-789]. On the other hand, the 5q translocation breakpoint disrupts the 3' UTR of MATR3, which encodes the nuclear matrix protein Matrin 3, and mouse Matr3 is strongly expressed in neural crest, developing heart and great vessels, whereas Ahdc1 is not. To further establish MATR3 3' UTR disruption as the cause of the proband's LVOT defects, we prepared a mouse Matr3(Gt-ex13) gene trap allele that disrupted the 3' portion of the gene. Matr3(Gt-ex13) homozygotes are early embryo lethal, but Matr3(Gt-ex13) heterozygotes exhibit incompletely penetrant BAV, CoA and PDA phenotypes similar to those in the human proband, as well as ventricular septal defect (VSD) and double-outlet right ventricle (DORV). Both the human MATR3 translocation breakpoint and the mouse Matr3(Gt-ex13) gene trap insertion disturb the polyadenylation of MATR3 transcripts and alter Matrin 3 protein expression, quantitatively or qualitatively. Thus, subtle perturbations in Matrin 3 expression appear to cause similar LVOT defects in human and mouse.

RNF213 variants in a child with PHACE syndrome and moyamoya vasculopathy.

Segmental infantile hemangiomas (IH) can be associated with congenital anomalies in a regional distribution. PHACE refers to large cervicofacial segmental IH in association with congenital anomalies of the aortic arch and medium-sized arteries of the head and neck, as well as structural anomalies of the posterior fossa and eye. A subset of PHACE patients have arterial anomalies that progress to moyamoya vasculopathy (MMV). MMV is defined as stenosis of the supraclinoid segment of the internal carotid arteries and/or their major branches, with subsequent development of a compensatory collateral vessel network. We describe a patient with MMV and segmental IH on the back and lower body who meets diagnostic criteria for PHACE based on a posterior segment eye anomaly and cerebral arterial anomalies. Whole exome sequencing demonstrated two inherited heterozygous variants in RNF213. Variants in RNF213 are associated with increased susceptibility to MMV. Our findings suggest that RNF213 variants may play a role in the development of MMV in patients with hemangioma syndromes associated with congenital cerebral arterial anomalies.

Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene.

A 200∼240 kb SH2B1-containing deletion region on 16p11.2 is associated with early-onset obesity and developmental delay. Here, we describe monozygotic twin brothers with discordant clinical presentations. Intrauterine fetal growth restriction was present in both twins. Additionally, twin A exhibited coarctation of aorta, left ventricular noncompaction, atrial septal defect, pericardial effusion, left hydronephrosis, and moderate developmental delay, whereas twin B exhibited single umbilical artery. Chromosome microarray analysis was performed on both twins and their parents. An identical 244 kb microdeletion on 16p11.2 including 9 Refseq genes, including SH2B1, was identified in the twins. The novel findings in monozygotic twins may expand the phenotypic spectrum of 16p11.2 microdeletion. Further studies are needed to strengthen the correlation between genotypes and abnormal clinical features.

Congenital heart defects in molecularly proven Kabuki syndrome patients.

The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%). Additional CHDs diagnosed in single patients included aortic dilatation with mitral anomaly and hypoplastic left heart syndrome. We also reviewed CHDs in patients with a molecular diagnosis of Kabuki syndrome reported in the literature. In conclusion, a CHD is detected in 70% of patients with KMT2D (MLL2) pathogenic variants, most commonly left-sided obstructive lesions, including multiple left-sided obstructions similar to those observed in the spectrum of the Shone complex, and septal defects. Clinical management of Kabuki syndrome should include echocardiogram at the time of diagnosis, with particular attention to left-sided obstructive lesions and mitral anomalies, and annual monitoring for aortic arch dilatation.

Systematic review and meta-analysis of persistent left superior vena cava on prenatal ultrasound: associated anomalies, diagnostic accuracy and postnatal outcome.

OBJECTIVES: To quantify the prevalence of chromosomal anomalies in fetuses with persistent left superior vena cava (PLSVC), assess the strength of the association between PLSVC and coarctation of the aorta and ascertain the diagnostic accuracy of antenatal ultrasound in correctly identifying isolated cases of PLSVC. METHODS: MEDLINE, EMBASE, CINHAL and the Cochrane databases were searched from the year 2000 onwards using combinations of keywords 'left superior vena cava' and 'outcome'. Two authors reviewed all abstracts independently. Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale for cohort studies. The rates of the following outcomes were analyzed: chromosomal abnormalities; associated intracardiac anomalies (ICAs) and extracardiac anomalies (ECAs) diagnosed prenatally; additional ICAs and ECAs detected only at postnatal imaging or clinical evaluation but missed at prenatal imaging; and association of PLSVC and coarctation of the aorta. Meta-analyses of proportions were used to combine data. RESULTS: In total, 2708 articles were identified and 13 (n = 501) were included in the systematic review. Associated ICAs and ECAs were detected at the prenatal ultrasound examination or at a follow-up assessment in 60.7% (95% CI, 44.2-75.9%) and 37.8% (95% CI, 31.0-44.8%) of cases, respectively. Chromosomal anomalies occurred in 12.5% (95% CI, 9.0-16.4%) of cases in the overall population of fetuses with PLSVC and in 7.0% (95% CI, 2.7-13.0%) of isolated cases. Additional ICAs and ECAs were detected only after birth and missed at ultrasound in 2.4% (95% CI, 0.5-5.8%) and 6.7% (95% CI, 2.2-13.2%) of cases, respectively. Coarctation of the aorta was associated with isolated PLSVC in 21.3% (95% CI, 13.6-30.3%) of cases. CONCLUSIONS: PLSVC is commonly associated with ICAs, ECAs and chromosomal anomalies. Fetuses with isolated PLSVC should be followed up throughout pregnancy in order to rule out coarctation of the aorta. As most of the data in this review were derived from high-risk pregnancies, the rate of associated abnormalities is likely to be higher than that in the general population of fetuses with PLSVC, for which more data are needed. Revisión sistemática y metaanálisis de la persistencia de la vena cava superior izquierda en la ecografía prenatal: anomalías asociadas, precisión del diagnóstico y resultado postnatal RESUMEN OBJETIVOS: Cuantificar la prevalencia de anomalías cromosómicas en fetos con vena cava superior izquierda persistente (VCSIP), evaluar la solidez de la asociación entre la VCSIP y la coartación aórtica, y determinar la precisión del diagnóstico de la ecografía prenatal como método para identificar correctamente casos aislados de VCSIP. MÉTODOS: Se buscó en las bases de datos de MEDLINE, EMBASE, CINHAL y Cochrane artículos publicados desde el año 2000 en adelante, usando combinaciones de las palabras clave "vena cava superior izquierda" y "resultado". Dos de los autores revisaron de forma independiente todos los resúmenes encontrados. La evaluación de calidad de los estudios incluidos se realizó mediante la escala Newcastle-Ottawa para estudios de cohortes. Se analizaron las tasas de los siguientes resultados: anomalías cromosómicas; anomalías intracardíacas (AIC) y anomalías extracardíacas (AEC) asociadas diagnosticadas prenatalmente; AIC y AEC adicionales detectadas sólo en ecografías postnatales o mediante evaluación clínica, pero no observadas en ecografías prenatales; y la asociación entre la VCSIP y la coartación aórtica. Se utilizó un meta-análisis de proporciones para combinar los datos. RESULTADOS: En total, se identificaron 2708 artículos y se incluyeron 13 (n = 501) en la revisión sistemática. En la ecografía prenatal o en una revisión de seguimiento se detectaron AIC y AEC asociadas en el 60,7% (IC 95%, 44,2-75,9%) y el 37,8% (IC 95%, 31,0-44,8%) de los casos, respectivamente. Se produjeron anomalías cromosómicas en el 12,5% (IC 95%, 9,0-16,4%) de los casos en la población general de fetos con VCSIP y en el 7,0% (IC 95%, 2,7-13,0%) de casos aislados. Las AIC y AEC adicionales sólo se detectaron después del nacimiento y en el 6,7% (IC 95%, 2,2-13,2%) de los casos, respectivamente. La coartación aórtica se encontró asociada con la VCSIP aislada en un 21,3% (IC 95%, 13,6-30,3%) de los casos. CONCLUSIONES: La VCSIP está comúnmente asociada a AIC, AEC y anomalías cromosómicas. Los fetos con VCSIP aislada deben ser objeto de seguimiento durante todo el embarazo, con el fin de descartar la coartación aórtica. Como la mayoría de los datos de esta revisión proceden de embarazos de alto riesgo, es probable que la tasa de anomalías asociadas sea más alta que la de la población general de fetos con VCSIP, por lo que se necesitan más datos.

Chromosomal abnormalities and copy number variations in fetal left-sided congenital heart defects.

OBJECTIVES: To demonstrate the spectrum of copy number variants (CNVs) in fetuses with isolated left-sided congenital heart defects (CHDs), and analyse genetic content. METHODS: Between 2003 and 2012, 200 fetuses were identified with left-sided CHD. Exclusion criteria were chromosomal rearrangements, 22q11.2 microdeletion and/or extra-cardiac malformations (n = 64). We included cases with additional minor anomalies (n = 39), such as single umbilical artery. In 54 of 136 eligible cases, stored material was available for array analysis. CNVs were categorized as either (likely) benign, (likely) pathogenic or of unknown significance. RESULTS: In 18 of the 54 isolated left-sided CHDs we found 28 rare CNVs (prevalence 33%, average 1.6 CNV per person, size 10.6 kb-2.2 Mb). Our interpretation yielded clinically significant CNVs in two of 54 cases (4%) and variants of unknown significance in three other cases (6%). CONCLUSIONS: In left-sided CHDs that appear isolated, with normal chromosome analysis and 22q11.2 FISH analysis, array analysis detects clinically significant CNVs. When counselling parents of a fetus with a left-sided CHD it must be taken into consideration that aside from the cardiac characteristics, the presence of extra-cardiac malformations and chromosomal abnormalities influence the treatment plan and prognosis.

MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development.

Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations.

Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity­ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas.

We report on a young girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas. These features are similar to those reported in individuals with variant forms of orofaciodigital syndrome known as congenital heart defects, hamartomas of the tongue and polysyndactly (CHDHTP: OMIM 217085) [Örstavik et al., 1992] and orocardiodigital syndrome [Digilio et al., 1996]. Whole exome sequencing revealed that she is a compound heterozygote for a frame shift mutation and a likely pathogenic sequence variant in WDPCP, a gene that regulates planar cell polarity and ciliogenesis. Results of genotyping in her parents and unaffected siblings were consistent with autosomal recessive inheritance of the mutation and the WDPCP variant. These results suggest that disruption of planar cell polarity and ciliogenesis may result in this unusual form of orofaciodigital syndrome.