Left-sided congenital heart disease (CHD) encompasses a spectrum of malformations that range from bicuspid aortic valve to hypoplastic left heart syndrome. It contributes significantly to infant mortality and has serious implications in adult cardiology. Although left-sided CHD is known to be highly heritable, the underlying genetic determinants are largely unidentified. In this study, we sought to determine the impact of structural genomic variation on left-sided CHD and compared multiplex families (464 individuals with 174 affecteds (37.5%) in 59 multiplex families and 8 trios) to 1,582 well-phenotyped controls. 73 unique inherited or de novo CNVs in 54 individuals were identified in the left-sided CHD cohort. After stringent filtering, our gene inventory reveals 25 new candidates for LS-CHD pathogenesis, such as SMC1A, MFAP4, and CTHRC1, and overlaps with several known syndromic loci. Conservative estimation examining the overlap of the prioritized gene content with CNVs present only in affected individuals in our cohort implies a strong effect for unique CNVs in at least 10% of left-sided CHD cases. Enrichment testing of gene content in all identified CNVs showed a significant association with angiogenesis. In this first family-based CNV study of left-sided CHD, we found that both co-segregating and de novo events associate with disease in a complex fashion at structural genomic level. Often viewed as an anatomically circumscript disease, a subset of left-sided CHD may in fact reflect more general genetic perturbations of angiogenesis and/or vascular biology.

Despite a wide range of clinical tools, the etiology of mental retardation and multiple congenital malformations remains unknown for many patients. Array-based comparative genomic hybridization (aCGH) has proven to be a valuable tool in these cases, as its pangenomic coverage allows the identification of chromosomal aberrations that are undetectable by other genetic methods targeting specific genomic regions. Therefore, aCGH is increasingly used in clinical genetics, both in the postnatal and the prenatal settings. While the diagnostic yield in the postnatal population has been established at 10-12%, studies investigating fetuses have reported variable results. We used whole-genome aCGH to investigate fetuses presenting at least one major malformation detected on ultrasound, but for whom standard genetic analyses (including karyotype) failed to provide a diagnosis. We identified a clinically significant chromosomal aberration in 8.2% of tested fetuses (4/49), and a result of unclear clinical significance in 12.2% of tested fetuses (6/49). Our results document the value of whole-genome aCGH as a prenatal diagnostic tool and highlight the interpretation difficulties associated with copy number variations of unclear significance.

Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene within this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype-phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.

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BackgroundMolecular karyotyping is now the first-tier genetic test for patients affected with unexplained intellectual disability (ID) and/or multiple congenital anomalies (MCA), since it identifies a pathogenic copy number variation (CNV) in 10-14% of them. High-resolution microarrays combining molecular karyotyping and single nucleotide polymorphism (SNP) genotyping were recently introduced to the market. In addition to identifying CNVs, these platforms detect loss of heterozygosity (LOH), which can indicate the presence of a homozygous mutation or uniparental disomy. Since these abnormalities can be associated with ID and/or MCA, their detection is of particular interest for patients whose phenotype remains unexplained. However, the diagnostic yield obtained with these platforms is not confirmed, and the real clinical value of LOH detection has not been established.MethodsWe selected 21 children affected with ID, with or without congenital malformations, for whom standard genetic analyses failed to provide a diagnosis. We performed high-resolution SNP array analysis with four platforms (Affymetrix Genome-Wide Human SNP Array 6.0, Affymetrix Cytogenetics Whole-Genome 2.7 M array, Illumina HumanOmni1-Quad BeadChip, and Illumina HumanCytoSNP-12 DNA Analysis BeadChip) on whole-blood samples obtained from children and their parents to detect pathogenic CNVs and LOHs, and compared the results with those obtained on a moderate resolution array-based comparative genomic hybridization platform (NimbleGen CGX-12 Cytogenetics Array), already used in the clinical setting.ResultsWe identified a total of four pathogenic CNVs in three patients, and all arrays successfully detected them. With the SNP arrays, we also identified a LOH containing a gene associated with a recessive disorder consistent with the patient’s phenotype (i.e., an informative LOH) in four children (including two siblings). A homozygous mutation within the informative LOH was found in three of these patients. Therefore, we were able to increase the diagnostic yield from 14.3% to 28.6% as a result of the information provided by LOHs.ConclusionsThis study shows the clinical usefulness of SNP arrays in children with ID, since they successfully detect pathogenic CNVs, identify informative LOHs that can lead to the diagnosis of a recessive disorder. It also highlights some challenges associated with the use of SNP arrays in a clinical laboratory.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-014-0070-0) contains supplementary material, which is available to authorized users.

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Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is an autosomal dominant condition characterized by multiple small capillary malformations (CM) and arteriovenous malformations (AVM) or arteriovenous fistulas (AVF). Prenatal presentation is a rare occurrence. Here, we report a young girl without AVM, who presented prenatally with polyhydramnios, pyelectasis, and pleural effusions. Postnatally, she had congenital chylothorax, growth retardation, and capillary malformations. Genetic testing identified a de novo pathogenic RASA1 variant. This case illustrates the highly variable phenotype of CM-AVM syndrome and suggests that it is likely underdiagnosed. A 41-year-old mother was referred to prenatal genetics for unilateral pleural effusion at 32 weeks of gestation. She was a healthy G4P1A1 who previously had a healthy 4-year-old girl and a miscarriage. The father was known for cluster headaches and the mother's brother died at 2 months after a fever. The current pregnancy was uneventful, with normal nuchal translucency and low-risk integrated trisomy 21 screening. Morphology ultrasound at 21 2/7 weeks showed right kidney pyelectasis and was otherwise normal. Control ultrasound at 32 weeks showed mild to moderate left pleural effusion, without any other abnormalities, including normal kidneys. Fetal cardiac ultrasound (32 3/7 weeks) was normal. Amniocentesis was declined. Non-invasive prenatal testing showed a low risk for trisomies 13, 18, and 21, and maternal