Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population

Abstract

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2,200 previously unpublished Saudi families as a first-tier test.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.

Keywords: autozygome; candidate genes; clinical genomics; dual diagnosis; exome; expanded carrier screening; fetal malformation; first-tier; genomics-first; gonadal mosaicism; hybrid phenotype; knockout; multilocus phenotypes; phenotypic expansion; prenatal.

Figure 1

Summary of the Study Cohort Characteristics (A) Age distribution. (B) Family history. (C) Testing strategy. (D) Ordering specialty. (E) Primary indication (prenatal in this figure includes individuals who presented for testing for carrier status). (F) ACMG classification of variants. (G) Mendelian patterns of pathogenic and likely pathogenic variants. (H) Multi-locus phenotypes.