A biallelic frameshift indel in PPP1R35 as a cause of primary microcephaly.

TitleA biallelic frameshift indel in PPP1R35 as a cause of primary microcephaly.
Publication TypeJournal Article
Year of Publication2023
AuthorsDawood, M, Akay, G, Mitani, T, Marafi, D, Fatih, JM, Gezdirici, A, Najmabadi, H, Kahrizi, K, Punetha, J, Grochowski, CM, Du, H, Jolly, A, Li, H, Coban-Akdemir, Z, Sedlazeck, FJ, Hunter, JV, Jhangiani, SN, Muzny, DM, Pehlivan, D, Posey, JE, Carvalho, CMB, Gibbs, RA, Lupski, JR
JournalAm J Med Genet A
Date Published2023 Mar
KeywordsCodon, Terminator, Frameshift Mutation, Humans, Infant, Newborn, Iran, Microcephaly, Microtubule-Associated Proteins, Pedigree

Protein phosphatase 1 regulatory subunit 35 (PPP1R35) encodes a centrosomal protein required for recruiting microtubule-binding elongation machinery. Several proteins in this centriole biogenesis pathway correspond to established primary microcephaly (MCPH) genes, and multiple model organism studies hypothesize PPP1R35 as a candidate MCPH gene. Here, using exome sequencing (ES) and family-based rare variant analyses, we report a homozygous, frameshifting indel deleting the canonical stop codon in the last exon of PPP1R35 [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]; the variant allele maps in a 3.7 Mb block of absence of heterozygosity (AOH) in a proband with severe MCPH (-4.3 SD at birth, -6.1 SD by 42 months), 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-house database of 14,000+ exomes including 1800+ Turkish exomes supporting predicted pathogenicity. Comprehensive literature searches for PPP1R35 variants yielded two probands affected with severe microcephaly (-15 SD and -12 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.

Alternate JournalAm J Med Genet A
PubMed ID36598158
PubMed Central IDPMC9928800
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States