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Several proteins in this centriole biogenesis pathway correspond to established primary microcephaly (MCPH) genes, and multiple model organism studies hypothesize <jats:italic>PPP1R35<\/jats:italic> as a candidate MCPH gene. Here, using exome sequencing (ES) and family\u2010based rare variant analyses, we report a homozygous, frameshifting indel deleting the canonical stop codon in the last exon of <jats:italic>PPP1R35<\/jats:italic> [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]; the variant allele maps in a 3.7\u00a0Mb block of absence of heterozygosity (AOH) in a proband with severe MCPH (\u22124.3 SD at birth, \u22126.1 SD by 42\u2009months), pachygyria, and global developmental delay from a consanguineous Turkish kindred. Droplet digital PCR (ddPCR) confirmed mutant mRNA expression in fibroblasts. In silico prediction of the translation of mutant PPP1R35 is expected to be elongated by 18 amino acids before encountering a downstream stop codon. This complex indel allele is absent in public databases (ClinVar, gnomAD, ARIC, 1000 genomes) and our in\u2010house database of 14,000+ exomes including 1800+ Turkish exomes supporting predicted pathogenicity. Comprehensive literature searches for <jats:italic>PPP1R35<\/jats:italic> variants yielded two probands affected with severe microcephaly (\u221215 SD and\u2009\u221212 SD) with the same homozygous indel from a single, consanguineous, Iranian family from a cohort of 404 predominantly Iranian families. The lack of heterozygous cases in two large cohorts representative of the genetic background of these two families decreased our suspicion of a founder allele and supports the contention of a recurrent mutation. We propose two potential secondary structure mutagenesis models for the origin of this variant allele mediated by hairpin formation between complementary GC rich segments flanking the stop codon via secondary structure mutagenesis.<\/jats:p>","DOI":"10.1002\/ajmg.a.63080","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T13:16:00Z","timestamp":1672838160000},"page":"794-804","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A biallelic frameshift indel in <i>PPP1R35<\/i> as a cause of primary microcephaly"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0192-1277","authenticated-orcid":false,"given":"Moez","family":"Dawood","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Human Genome Sequencing Center Baylor College of Medicine  Houston Texas 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