An uncommon inheritance pattern in Niemann-Pick disease type C: identification of probable paternal germline mosaicism in a Mexican family

Abstract

BackgroundNiemann-Pick disease type C (NP-C) is a fatal lysosomal neurodegenerative and neurovisceral disease. It is caused by defects in intracellular lipid trafficking, which lead to the accumulation of lipids and glycosphingolipids within the endosomes and lysosomes of affected individuals. Pathogenic variants of the NPC1 or NPC2 genes yield highly variable phenotypes with a time course that ranges from fetal onset (i.e., hydrops fetalis) to progressive dementia in adults. NP-C is typically inherited in an autosomal-recessive manner. To our knowledge, no previous report has identified germline mosaicism as an inheritance mechanism in NP-C.Case presentationWe report the case of a male Mexican patient with “variant” filipin staining and a juvenile form of NP-C attributed to compound heterozygosity for two previously reported pathogenic variants of NPC1: c.[1042C>T];[2780C>T] or p.[Arg348*];[Ala927Val]. The proband’s mother and healthy sister were heterozygous carriers of the c.2780C > T (exon 18) and c.1042C > T (exon 8) variants, respectively. However, direct sequencing of exons 8 and 18 of NPC1 revealed no mutation in genomic DNA obtained from the father’s peripheral blood. DNA profiling ruled out the possibility of non-paternity. We were unable to obtain a sperm sample to demonstrate paternal gonadal mosaicism. NPC1 haplotype analysis using 20 linked single nucleotide variants failed to yield sufficient information to document a p.(Arg348*) NPC1 pathogenic variant-associated haplotype in the family.ConclusionsWe propose that this case of NP-C involves paternal germline mosaicism. To the best of our knowledge, this has not previously been reported in NP-C.

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease

“…In NP-C cohorts from the UK, Europe and Australia, 22-38% of cases were related [6,7,32]. However, the high proportion of NP-C patients with compound heterozygote genotypes makes the study of genotype-phenotype correlations challenging [39,40,41]. NP-C symptoms can vary widely among family members, even in those with identical genetic mutations.…”

Germline mosaicism in a collagen VI‐related myopathy family: A cause of autosomal recessive inheritance

“…This is the reason why germline mosaicism has been much less reported in autosomal recessive diseases than in autosomal dominant diseases. 5,6 In addition to having major clinical implication in assessing recurrence risk of future pregnancies in such families, this scenario has other implication as interest grows in the use of carrier screening in reproductive medicine. When a pathological recessive allele is detected in only one partner, couples will be told that the recurrence risk for the offspring is almost none.…”