Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

摘要

A The pedigree structure of families A and segregation of GBA: c.115+1G>A and DNAJB6; p.T193A (c.A577G) are shown. Affected individuals are shown as filled symbols and the arrow points to the index patient. The affection status of the family members of generation I and II could not be ascertained. The affection status of deceased individuals (diagonal lines) was reported by immediate family members and was confirmed by available medical records. Symbols with black lines (IV:6, V:4, and V:5) indicate asymptomatic GBA variant carriers. Asterisks mark the individuals for whom whole-genome sequencing and rare variant analysis was performed. B Representative Sanger sequence chromatograms showing GBA1: c.115+1G>A and DNAJB6; p.T193A (c.A577G) variant positions in subjects IV:4 and IV:7 of family A. Arrowhead points to heterozygous substitutions. C The pedigree structure of families B and segregation of GBA; p.L444P (c.1448T>C) and PSAP; p.N157S (c.A470G) variants is shown. Affected individuals are shown as filled symbols and the arrow points to the index patients. The symbol with a white circle indicates an individual with PD but without GBA variant (phenocopy PD patient, III:4). The PSAP; p.N157S (c.A470G) variant was found in all PD, and in addition in one healthy family member (IV:7). Asterisks mark the individuals for whom whole-genome sequencing and rare variant analysis was performed. D Representative sanger sequence chromatograms showing GBA; p.L444P (c.1448T>C) and PSAP; p.N157S (c.A470G) variant positions in subjects III:1 and III:2 of family B. Arrowhead points to heterozygous substitutions.