Genetic basis of neurodevelopmental disorders in 103 Jordanian families

Abstract

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in‐house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease‐causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.

Clinical and molecular delineation of PUS3‐associated neurodevelopmental disorders

“…Facial dysmorphisms was reported in 17 out of 18 individuals, but a recognizable facial dysmorphism was not observed (Figure 1). Gray sclera was detected in six previously reported individuals from three families, 8,12,14 and among the newly described patients we have observed blue/gray sclera in a single individual (individual 7). Even though this feature does not seem to be frequent among the 20 liveborn individuals, it may be present subtly.…”

Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy

“…Exome sequencing was performed on genomic DNA samples as previously described 5 . In brief, coding regions were enriched using SureSelectXT™ Human All Exon kit (AGILENT®, v6/7) for subsequent sequencing as paired‐end reads on an Illumina® platform (NextSeq500™, HiSeq2500, NovaSeq6000).…”

Detection of mobile elements insertions for routine clinical diagnostics in targeted sequencing data

“…We scanned for MEIs in 2,504 WES samples prepared with Agilent SureSelect Human All Exon v6 and 5,189 WES prepared with Agilent SureSelect Human All Exon v7 hybridcapture kits. Samples were processed uniformly and sequenced to around 130x average read coverage, as described previously (Froukh et al, 2020).…”