title: Segmental uniparental isodisomy of chromosome 6 causing transient diabetes mellitus and merosin-deficient congenital muscular dystrophy.
abstract: Segmental uniparental isodisomy (iUPD) is a rare genetic event that may cause aberrant expression of imprinted genes, and reduction to homozygosity of a recessive mutation. Transient neonatal diabetes mellitus (TNDM) is typically caused by imprinting aberrations in chromosome 6q24 TNDM differentially-methylated region (DMR). Approximately, 15.12 Mb upstream in 6q22-q23 is located LAMA2, the gene responsible of merosin-deficient congenital muscular dystrophy type 1A (MDC1A). We investigated a patient diagnosed both with TNDM and MDC1A, born from a twin dichorionic discordant pregnancy. Parents are first-degree cousins. Methylation sensitive-PCR of the imprinted 6q24 TNDM CpG island showed only the non-methylated (paternal) allele. Microsatellite markers and SNP array profiling disclosed normal biparental inheritance at 6p and a segmental paternal iUPD, between 6q22.33 and 6q27. Sequencing of LAMA2 exons showed a homozygous frameshift mutation, c.7490_7493dupAAGA, which predicts p.Asp2498GlufsX4, in exon 54. Her father, but not her mother, was a carrier of the mutation. While segmental paternal iUPD6 causing TNDM was reported twice, there are no previous reports of MDC1A caused by this event. This is a child with two genetic disorders, yet neither is caused by the parental consanguinity, which reinforces the importance of considering different etiological mechanisms in the genetic clinic.
authors.affiliation: Genetics Division, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: Raissa Coelho
authors.initials: RC
authors.lastname: Andrade
authors.forename: Julián
authors.initials: J
authors.lastname: Nevado
authors.forename: Maria Angélica
authors.initials: MA
authors.lastname: de Faria Domingues de Lima
authors.forename: Tânia
authors.initials: T
authors.lastname: Saad
authors.forename: Lucia
authors.initials: L
authors.lastname: Moraes
authors.forename: Leila
authors.initials: L
authors.lastname: Chimelli
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.forename: Fernando Regla
authors.initials: FR
authors.lastname: Vargas
mesh_terms: D000328:Adult; D002896:Chromosomes, Human, Pair 6; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D007223:Infant; D007797:Laminin / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats; D009136:Muscular Dystrophies / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D024182:Uniparental Disomy
chemical_list: D007797:Laminin; C102645:laminin alpha 2
keywords: 6q24 segmental uniparental disomy; LAMA2; MDC1A; TNDM