Neuropediatrics 2004; 35 - P66
DOI: 10.1055/s-2004-819440

A heterozygous genomic rearrangement in a patient with juvenile spinal muscle atrophy with respiratory distress type 1 (SMARD1)

UP Guenther 1, 2, M Schuelke 1, E Bertini 3, K Grohmann 1, C Hübner 1, R Varon 2
  • 1Department of Pediatric Neurology, Charité, Medical School Berlin, Germany
  • 2Institute of Human Genetics, Charité, Medical School Berlin, Germany
  • 3Department of Neuroscience and Unit of Molecular Medicine, Bambino Gesu’ Children's Hospital, Rome, Italy

Introduction: Autosomal recessive SMARD1 is caused by mutations of the IGHMBP2 gene. In infantile SMARD1, observed mutations include missense and nonsense mutations, short insertions, and deletions. Here, we characterize the genotype of the first patient with juvenile SMARD1.

Methods: Southern blot and RT-PCR experiments indicated a rearrangement of the IGHMBP2 gene, that was subsequently confirmed and characterized at genomic and cDNA level by sequencing.

Results: We identified a missense mutation on the maternal allele and a large genomic deletion on the paternal allele. Breakpoint analysis revealed an Alu/Alu mediated rearrangement resulting in a loss of 18,5 kb between intron 2 and intron 7 of IGHMBP2. This results in an in-frame-deletion at the mRNA level including exons 3 to 7.

Conclusion: We demonstrate that SMARD1 patients can harbor genomic rearrangements at the IGHMBP2 gene locus, a finding that may be easily missed by gene sequencing. Moreover, the large heterozygous in-frame deletion in IGHMBP2 can cause a hitherto unknown juvenile course of SMARD1.

Keywords: juvenile SMARD1, IGHMBP2, genomic rearrangement