Mosaic parental germline mutations causing recurrent forms of malformations of cortical development

Abstract

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.

Figure 1

Families with parental germline mosaic variants. (a) P248-STX7 variant. (a1, a2, a3) Proband's MRI sections showing the extended heterotopic band. (a4) WES reads showing the STX7 variant and one variant read in the father. (a5) Droplet digital PCR data confirming the somatic mosaicism in the father: variant allele is present in 213 out of 3882 positive droplets in first father well; 207 out of 3788 in second well; 239 out of 3738 in third well; absent in the mother and present in 1982 out of 2053 droplets in the proband. (a6) Father's MRI showing the milder posterior band heterotopia (arrow). (b) P474-TUBA1A variant. (b1, b2, b3) Patient's MRI sections showing the corpus callosum agenesis, brainstem and cerebellum abnormalities, bilateral opercular dysplasia and dysmorphic ventricular horns. (c) P374-DYNC1H1 mutation. (c1, c2) Histopathological sections showing heterotopic neuronal cells, extended polymicrogyria, enlarged germinative zones and disorganized axonal tracts (arrows). (d) P5-DYNC1H1 variant. Star symbol is to highlight position of heterozygous mutation in affected individuals.