title: An uncommon inheritance pattern in Niemann-Pick disease type C: identification of probable paternal germline mosaicism in a Mexican family.
abstract: BACKGROUND
  Niemann-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.
  
  
  METHODS
  We 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Departamento de Genética Médica, Centro de Rehabilitación e Inclusión Infantil Teletón, Vía Gustavo Baz No. 219, Colonia San Pedro Barrientos, Tlalnepantla, Estado de México, 54960, México. gcervera@teleton.org.mx.
authors.forename: Marivi
authors.initials: M
authors.lastname: Cervera-Gaviria
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México.|DNA-GEN, S.C. Centro de Alta Especialidad en Genética Humana, Ciudad de México, México.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Alcántara-Ortigoza
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México.|DNA-GEN, S.C. Centro de Alta Especialidad en Genética Humana, Ciudad de México, México.
authors.forename: Ariadna
authors.initials: A
authors.lastname: González-Del Angel
authors.affiliation: Departamento de Genética Médica, Centro de Rehabilitación e Inclusión Infantil Teletón, Vía Gustavo Baz No. 219, Colonia San Pedro Barrientos, Tlalnepantla, Estado de México, 54960, México.
authors.forename: Paola
authors.initials: P
authors.lastname: Moyers-Pérez
authors.affiliation: Departamento de Rehabilitación Pediátrica, Centro de Rehabilitación e Inclusión Infantil Teletón, Estado de México, México.
authors.forename: Blanca Gabriela Lizet
authors.initials: BG
authors.lastname: Legorreta-Ramírez
authors.affiliation: Departamento de Neuropediatría, Centro de Rehabilitación e Inclusión Infantil Teletón, Estado de México, México.
authors.forename: Nancy
authors.initials: N
authors.lastname: Barrera-Carmona
authors.affiliation: Servicio de Medicina Interna, Sociedad de Beneficencia Española, Ciudad de México, México.
authors.forename: Jaime
authors.initials: J
authors.lastname: Cervera-Gaviria
mesh_terms: D005091:Exons; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D009030:Mosaicism; D009154:Mutation; D052556:Niemann-Pick Disease, Type C / Q000235:genetics*; D011336:Probability; D055815:Young Adult
keywords: Genetic counseling; Germline mosaicism; Lysosomal storage disease; NPC1 mutations; Niemann-Pick disease type C