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Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology., (© 2022 Wiley Periodicals LLC.)

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Familial Ebstein anomaly is a rare form of congenital heart disease. We report 7 individuals among 2 generations of 1 family with Ebstein anomaly. This family was first reported in 1991 by Balaji et al in which family members were also reported to have a mild skeletal phenotype. The most likely mechanism of inheritance was concluded to be autosomal dominant. We sought to identify the genetic pathogenesis in this family using a next generation sequencing approach., Methods and Results: Whole exome sequencing was performed in 2 cousins in this family using the Agilent SureSelect Human all Exon 51 Mb version 5 capture kit. Data were processed through an analytic in-house pipeline. Whole exome sequencing identified a missense mutation in FLNA (Filamin A), an actin-binding protein located at Xq28, mutations in which are associated with the skeletal phenotypes Frontometaphyseal dysplasia, Otopalatodigital, and Melnick-Needles syndrome, with X-linked periventricular nodular heterotopia and FG syndrome (Omim, 305450). Review of the phenotypes of those with the mutation in this family shows increased severity of the cardiac phenotype and associated skeletal features in affected males, consistent with X-linked inheritance., Conclusions: Although congenital heart disease is reported in families with mutations in FLNA , this is the first report of individuals being affected by Ebstein anomaly because of a mutation in this gene and details the concurrent skeletal phenotype observed in this family., (© 2017 American Heart Association, Inc.)

Congenital heart defects (CHD) are present in over 1% of all newborns and are the leading cause of birth-defect-related deaths in the United States. We describe two male subjects with CHD, one with an atrial septal defect, a ventricular septal defect, and pulmonary artery stenosis; and the other with tetralogy of Fallot and a right aortic arch, who carry partially overlapping, de novo deletions of chromosome 5q33. The maximum region of overlap between these deletions encompasses HAND1 and SAP30L, two genes that have previously been shown to play a role in cardiac development. HAND1 encodes a basic helix-loop-helix transcription factor. Cardiac-specific ablation of Hand1 in mice causes septal, valvular, and outflow tract defects. SAP30L, its paralog SAP30, and other SAP proteins form part of a multi-subunit complex involved in transcriptional regulation via histone deacetylation. Morpholino knockdown of sap30L in zebrafish, which do not have a distinct sap30 gene, leads to cardiac hypoplasia and cardiac insufficiency. We subsequently identified two other individuals with chromosomal deletions involving HAND1 and SAP30L in whom cardiac-related medical problems were not described. These observations suggest that haploinsufficiency of HAND1 and/or SAP30L may contribute to the development of CHD, although the contribution of other genes on chromosome 5q33 cannot be excluded. Our findings also suggest that the penetrance of CHD associated with 5q33 deletions is incomplete and may be influenced by other genetic, environmental or stochastic factors. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s)., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Integrity of the long arm of the X chromosome is important for maintaining female fertility and several critical regions for normal ovarian function have been proposed. In order to understand further the importance of specific areas of the X chromosome, we describe a series of 20 previously unreported patients missing part of Xq in whom detailed phenotypic information has been gathered as well as precise chromosome mapping using array Comparative Genomic Hybridization. Features often associated with Turner syndrome were not common in our study and excluding puberty, menarche and menstruation, the phenotypes observed were present in only a minority of women and were not specific to the X chromosome. The most frequently occurring phenotypic features in our patients were abnormalities of menstruation and fertility. Larger terminal deletions were associated with a higher incidence of primary ovarian failure, occurring at a younger age; however patients with similar or even identical deletions had discordant menstrual phenotypes, making accurate genetic counselling difficult. Nevertheless, large deletions are likely to be associated with complete skewing of X inactivation so that the resulting phenotypes are relatively benign given the amount of genetic material missing, even in cases with unbalanced X;autosome translocations. Some degree of ovarian dysfunction is highly likely, especially for terminal deletions extending proximal to Xq27. In conjunction with patient data from the literature, our study suggests that loss of Xq26-Xq28 has the most significant effect on ovarian function., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans., Methods and Results: This study reports a large family in which two cousins with micro/anophthalmia each gave birth to at least one child with otocephaly, suggesting a genetic relationship between anophthalmia and otocephaly. OTX2, a known microphthalmia locus, was screened in this family and a frameshifting mutation was found. The study subsequently identified in one unrelated otocephalic patient a sporadic OTX2 mutation. Because OTX2 mutations may not be sufficient to cause otocephaly, the study assayed the potential of otx2 to modify craniofacial phenotypes in the context of known otocephaly gene suppression in vivo. It was found that otx2 can interact genetically with pgap1, prrx1, and msx1 to exacerbate mandibular and midline defects during zebrafish development. However, sequencing of these loci in the OTX2-positive families did not unearth likely pathogenic lesions, suggesting further genetic heterogeneity and complexity., Conclusion: Identification of OTX2 involvement in otocephaly/dysgnathia in humans, even if loss of function mutations at this locus does not sufficiently explain the complex anatomical defects of these patients, suggests the requirement for a second genetic hit. Consistent with this notion, trans suppression of otx2 and other developmentally related genes recapitulate aspects of the otocephaly phenotype in zebrafish. This study highlights the combined utility of genetics and functional approaches to dissect both the regulatory pathways that govern craniofacial development and the genetics of this disease group.

Background: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy., Methods: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region., Results: The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients., Conclusions: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.

We report an adult female with a left polycystic kidney, patent ductus arteriosus, left streak ovary, bicornuate uterus and deafness who presented with infertility. She has an intrachromosomal triplication of bands 2q12.3 to 2q13, with inversion of the central segment, which arose de novo from a paternal interchomosomal event. The triplication contains 68 known genes within the 7.28 Mb of DNA between base pairs 107,140,721 and 114,416,131. All intrachromosomal triplications are rare and, while partial duplications of 2q have been previously described, this patient is a unique surviving case of a triplication of proximal 2q., (Copyright 2009 S. Karger AG, Basel.)

We report two brothers, their mother and a maternal cousin who had a distinctive facial phenotype, mild brachydactyly and prominence of the interphalangeal joints. One brother and the mother also had multiple ventricular extrasystoles. Six other relatives in four generations were probably affected on the basis of history and family photographs. We also report a further individual from a different family with a similar facial phenotype, Pierre-Robin sequence, tapering fingers and multiple ventricular extrasystoles. These families have some similarities to those reported by Stoll et al. in a single family, showing dominant inheritance. Our patients would seem to have the same or a related condition.