Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD)

TY - JOUR

T1 - Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD)

T2 - defining novel phenotypes through hierarchical cluster analysis

AU - Guenther, Ulf-Peter

AU - Varon, Raymonda

AU - Schlicke, Maria

AU - Dutrannoy, Véronique

AU - Volk, Alexander

AU - Hübner, Christoph

AU - von Au, Katja

AU - Schuelke, Markus

N1 - (c) 2007 Wiley-Liss, Inc.

PY - 2007/8

Y1 - 2007/8

N2 - Autosomal recessive spinal muscular atrophy with respiratory distress (SMARD) is a heterogeneous disorder. Mutations in the immunoglobulin micro-binding protein gene (IGHMBP2) lead to SMARD1, but clinical criteria that delineate SMARD1 from other SMARD syndromes are not well established. Here we present a retrospective clinical and genetic study to determine the criteria that would predict the presence or absence of IGHMBP2 mutations. From 141 patients with respiratory distress and a spinal muscular atrophy phenotype we recorded the clinical features through a questionnaire and sequenced the entire coding region of IGHMBP2. In 47 (33%) patients we identified IGHMBP2 mutations, 14 of which were not described before. Clinical features and combinations thereof associated with the presence of IGHMBP2 mutations were discovered through hierarchical cluster analysis. This method detects common traits not evident at first sight by grouping items according to their similarity. The combination of "manifestation of respiratory failure between 6 weeks and 6 months" AND ("presence of diaphragmatic eventration" OR "preterm birth") predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. Non-SMARD1 patients fell into two different symptom clusters, mainly separated by the age at respiratory failure and the presence of multiple congenital contractures. The 14 novel IGHMBP2 mutations comprised missense, frameshift, splice-site, and nonsense mutations. All missense mutations altered conserved residues within or adjacent to the putative DNA helicase domain. The c.1235+3A>G splice-site mutation did not entirely suppress correct splicing and we found a residual wild-type IGHMBP2 mRNA steady-state level of 24.4+/-6.9%, which was, however, not sufficient to avert SMARD1 in this patient.

AB - Autosomal recessive spinal muscular atrophy with respiratory distress (SMARD) is a heterogeneous disorder. Mutations in the immunoglobulin micro-binding protein gene (IGHMBP2) lead to SMARD1, but clinical criteria that delineate SMARD1 from other SMARD syndromes are not well established. Here we present a retrospective clinical and genetic study to determine the criteria that would predict the presence or absence of IGHMBP2 mutations. From 141 patients with respiratory distress and a spinal muscular atrophy phenotype we recorded the clinical features through a questionnaire and sequenced the entire coding region of IGHMBP2. In 47 (33%) patients we identified IGHMBP2 mutations, 14 of which were not described before. Clinical features and combinations thereof associated with the presence of IGHMBP2 mutations were discovered through hierarchical cluster analysis. This method detects common traits not evident at first sight by grouping items according to their similarity. The combination of "manifestation of respiratory failure between 6 weeks and 6 months" AND ("presence of diaphragmatic eventration" OR "preterm birth") predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. Non-SMARD1 patients fell into two different symptom clusters, mainly separated by the age at respiratory failure and the presence of multiple congenital contractures. The 14 novel IGHMBP2 mutations comprised missense, frameshift, splice-site, and nonsense mutations. All missense mutations altered conserved residues within or adjacent to the putative DNA helicase domain. The c.1235+3A>G splice-site mutation did not entirely suppress correct splicing and we found a residual wild-type IGHMBP2 mRNA steady-state level of 24.4+/-6.9%, which was, however, not sufficient to avert SMARD1 in this patient.

KW - Chi-Square Distribution

KW - Cluster Analysis

KW - Cohort Studies

KW - DNA Mutational Analysis

KW - DNA, Complementary

KW - DNA-Binding Proteins

KW - Gene Expression Regulation

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Muscular Atrophy, Spinal

KW - Mutation

KW - Phenotype

KW - Respiration Disorders

KW - Transcription Factors

U2 - 10.1002/humu.20525

DO - 10.1002/humu.20525

M3 - SCORING: Journal article

C2 - 17431882

VL - 28

SP - 808

EP - 815

JO - HUM MUTAT

JF - HUM MUTAT

SN - 1059-7794

IS - 8

ER -