We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

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SLC25A42 gene encodes an inner mitochondrial membrane protein that imports Coenzyme A into the mitochondrial matrix. A mutation in this gene was recently reported in a subject born to consanguineous parents who presented with mitochondrial myopathy with muscle weakness and lactic acidosis. In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy. Our report confirms the link between SLC25A42 and mitochondrial disease in humans, and suggests that pathogenic variants in SLC25A42 should be interpreted with the understanding that the associated phenotype may be highly variable.

Hypomyelinating leukodystrophies are one of the white matter disorders caused by a lack of myelin deposition in the central nervous system (CNS). Here, we report the first case of hypomyelinating leukodystrophy in the Middle East and Saudi Arabia. This condition is caused by a mutation in the TMEM106B gene (HLD16; MIM 617964). Hypotonia, congenital nystagmus, delayed motor development, and delayed speech are the main clinical manifestations. The affected patient has mild pyramidal syndrome, a mild intellectual disability, ataxic gait, hyperreflexia, intention tremor, dysmetria, and other motor difficulties. Findings from neuroimaging reveal severe, ongoing, and diffuse hypomyelination identified via the whole exome sequencing, a harmful missense mutation in the TMEM106B gene that is heterozygous. The patient is the offspring of two unrelated persons. The protein's cytoplasmic domain contains a variation that is located in highly conserved residues. In an oligodendroglial cell line, the mutant protein significantly lowered the mRNA production of important myelin genes, decreased branching, and increased cell mortality. TMEM106B is abundantly expressed in neurons and oligodendrocytes in the CNS and is localized in the late endosome and lysosome compartments. TMEM106B levels can be controlled at the transcriptional level through chromatin modification, at the mRNA level through miRNAs, and at the protein level through lysosomal functions. Our findings reveal a novel role of zinc homeostasis in oligodendrocyte development and myelin production and show that variations in TMEM163 induce hypomyelination leukodystrophy.