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1.
Am J Med Genet A ; 176(1): 161-166, 2018 01.
Article in English | MEDLINE | ID: mdl-29150894

ABSTRACT

Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype.


Subject(s)
Bone and Bones/abnormalities , Cleft Palate/diagnosis , Cleft Palate/genetics , Craniosynostoses/diagnosis , Craniosynostoses/genetics , Dwarfism/diagnosis , Dwarfism/genetics , Genetic Association Studies , Limb Deformities, Congenital/diagnosis , Limb Deformities, Congenital/genetics , Lordosis/diagnosis , Lordosis/genetics , Adult , Child , Facies , Female , Genotype , Humans , Karyotype , Male , Mexico , Mutation , Phenotype , Receptor, Fibroblast Growth Factor, Type 3/genetics , Sequence Analysis, DNA , Syndrome , Tomography, X-Ray Computed
2.
BMC Neurol ; 16(1): 147, 2016 Aug 22.
Article in English | MEDLINE | ID: mdl-27549128

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. CASE PRESENTATION: 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.


Subject(s)
Inheritance Patterns , Mosaicism , Niemann-Pick Disease, Type C/genetics , Exons , Humans , Male , Mutation , Probability , Young Adult
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