How Many Genes Does It Take?

culturally isolated regions. In such populations, consanguineous marriages occur more frequently, which result in a higher burden of single-gene recessive and complex diseases [Bittles and Black, 2010]. ASDs are a quintessential form of such inherited complex neurodevelopmental disorders [Lichtenstein et al., 2010; Lyall et al., 2017]. Numerous studies of ASD patients have identified mutations affecting genes involved in regulating transcription, mRNA translation, protein synthesis and degradation as well as synaptic function, which apparently converge on cellular pathways affecting neuronal and synaptic homeostasis [Huguet and Bourgeron, 2013; Pinto et al., 2014; Bourgeron, 2015]. Yet, it is often difficult to pinpoint a single locus or gene that may be responsible for ASD in a single or several patients within a family [Salyakina et al., 2011; van Daalen et al., 2011]. In examining the pedigrees of families with ASD patients, one is often left with the impression that in addition to a de novo CNV, some undiscovered “susceptibility factor” may have been “missed. ” Concurrent searches for SNVs and CNVs in genome sequencing data of ASD patients showed that an appreciable number of them carried 3 or even more de novo variants [Turner et al., 2017]. However, most pedigrees are too small to allow for rigorous linkage analysis. By combining WES with homozygosity mapping in families selected for likely recessive inheritance of ASD, the number of genomic segments were narrowed down to those that cosegregated with disease, which allowed to pinpoint biallelic mutations in plausible candidate genes [Yu et al., 2013]. In a family with 2 boys with ASD and facial and skeletal anomalies, 3 phenotypically relevant loci have been Clinical genetics examine the pedigrees of families with a patient according to the mendelian framework of autosomal recessive, dominant, or X-linked inheritance. In case no evidence for inheritance can be found, the patient is considered to be sporadic and a search for de novo copy number variants (CNVs) or single nucleotide variants (SNVs) is initiated. Implicitly, clinical genetics follows the paradigm that one mutated gene must be involved in one disorder. Thus, clinical geneticists search for “the” gene to be held responsible for “this” specific disorder. To identify this specific gene, genome-wide screening for CNVs or whole-exome screening (WES), and even whole-genome sequencing are used. In addition, novel disease loci are pinpointed by genome-wide association studies (GWAS) of cohorts of patients. While family-based studies of individuals or a few patients uncovered rare, often unique, CNVs and SNVs, GWAS rely on common variants among the SNPs studied. To aid in clinical decision-making, the hundreds of genes identified in studies of cohorts of patients with autism spectrum disorders (ASDs) were classified according to chromosomal location, the way by which they were discovered, and a score for their strength of association with ASD (https://gene.sfari.org/database/human-gene/). With these efforts, 2 unexpected “by-products” arose. Using SNP arrays, designed to be heterozygous for all SNPs, to search for CNVs in the genome of a patient, incidentally regions of homozygous alleles were encountered. Such regions of homozygous SNPs reflect a close genetic relationship between the parents. These emerge in small populations on islands or other geographically or Received: April 7, 2020 Accepted: April 7, 2020 Published online: April 22, 2020