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. Author manuscript; available in PMC: 2024 Mar 1.
Published in final edited form as: Am J Med Genet A. 2023 Jan 4;191(3):794–804. doi: 10.1002/ajmg.a.63080

Figure 2. Pedigrees, genotyping, and phenotyping of BAB9269, M8600491 III:2, and M8600491 III:3 for candidate disease gene PPP1R35.

Figure 2

(A) Pedigree of Turkish family with PPP1R35 genotype indicated, proband identified by black arrow, and affected individuals shaded black. Sanger sequencing confirms autosomal recessive Mendelian segregation of the complex indel PPP1R35 [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]. (B) Microcephaly of proband BAB9269 shown at 1 week, 5 months, and 3 years and 5 months after birth. Microcephaly-related dysmorphic features including a sloped forehead, large and constricted ears, a smooth long philtrum, and micrognathia can be appreciated. (C) Mid-sagittal T2 sequence showing extremely small head size consistent with primary microcephaly, foreshortening and thinning of corpus callosum (red arrow) and mild to moderate cerebellar volume loss that is most prominent at the superior vermis. (D) Axial T2 sequence showing increased extra-axial CSF spaces, pachygyria with anterior posterior gradient (top green arrow points to left frontal lobe at the anterior aspect, and bottom green arrow points to left parietal lobe at the posterior aspect of the gradient), dysmorphic ventricular system and abnormal delayed myelination of the internal capsule. (E) Coronal T2 sequence showing generous extra-axial CSF spaces, pachygyria, lack of myelination for age cerebellar volume loss. Red arrow shows prominence of left cerebellar folia. (F) Plot of ratio of reads containing variants versus chromosome 7 genomic coordinates for BAB9269 with absence of heterozygosity (AOH) shaded in grey overlaps 3.7 Mb. Location of PPP1R35 variant contained within AOH region is displayed by the red horizontal bar. (G) Droplet digital PCR showed comparable gene expression of the mutant and wild-type alleles in fibroblasts of family members confirming expression of the mutant mRNA. (H) Pedigree of Iranian family with PPP1R35 genotype indicated, affected individuals shaded black. Sanger sequencing confirms autosomal recessive Mendelian segregation of the complex indel PPP1R35 [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]. (I) Microcephaly-related dysmorphic features including sloping forehead, large nose, maxillary hyperplasia, and misalignment of teeth can be appreciated.