Identification of novel candidate disease genes from de novo exonic copy number variants

Abstract

BackgroundExon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype–phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.MethodsWe retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.ResultsIn this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.ConclusionsTogether, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0472-7) contains supplementary material, which is available to authorized users.

EFNB2haploinsufficiency causes a syndromic neurodevelopmental disorder

“…Mice deficient in ephrin‐B ligands have defective radial neuronal migration with a pattern of neurons similar to those observed in mice lacking Reelin . DD or ID is present in all patient reported with 13q33 deletion encompasssing EFNB2 . In this report, patient B.II.1 (who carried the de novo mutation) and three patients out of four deletion carriers in family A have mild to moderate ID.…”

“…In this report, patient B.II.1 (who carried the de novo mutation) and three patients out of four deletion carriers in family A have mild to moderate ID. Developmental regression and autistic spectrum disorder had also been described in a male patient with a similar de novo deletion encompassing ARGLU1 and EFNB2 (Patient 1). Seizure was also reported in larger deletions, associated with microcephaly, moderate to severe ID .…”

“…ARGLU1 haploinsufficiency could also contribute to the neurodevelopmental phenotype including DD/ID. A de novo variant in ARGLU1 was identified in a male patient with neurological anomalies such as abnormal movement, cerebellar hypoplasia, and oculomotor apraxia …”

“…A de novo variant in ARGLU1 was identified in a male patient with neurological anomalies such as abnormal movement, cerebellar hypoplasia, and oculomotor apraxia. 24…”

Homozygous loss‐of‐function variants of TASP1 , a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies

“…The first child was a 4‐year‐old boy with global developmental delay, hypotonia, microcephaly, feeding difficulties, drooling, failure‐to‐thrive, recurrent respiratory infections, cryptorchidism, cardiovascular malformations (atrial septal defect [ASD] and ventricular septal defect [VSD]), hearing impairment in the right ear, clinodactyly, left single palmer crease, brachydactyly, excessive hair on trunk and extremities, a happy demeanor with frequent laughing and clapping, and distinctive facial features (Figure a; Supporting Information Clinical Data). Chromosomal microarray (CMA), performed at Baylor Genetics Laboratory, Houston, TX as previously described (Gambin et al, ), revealed a homozygous deletion at 20p12.1 corresponding to a minimum deletion boundary of chr20:13,463,860‐13,532,560 (hg19) (Figure S1A) . The minimum deleted region (69 kb) only included exons 9–11 of TASP1 (NM_017714.2).…”