Segmental Uniparental Isodisomy of Chromosome 6 Causing Transient Diabetes Mellitus and Merosin-Deficient Congenital Muscular Dystrophy

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, 15.12Mb 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. (c) 2014 Wiley Periodicals, Inc.