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Mutation-based growth charts for SEDC and other COL2A1 related dysplasias

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Author: Terhal, P.A. · Dommelen, P. van · Le Merrer, M. · Zankl, A. · Simon, M.E. · Smithson, S.F. · Marcelis, C. · Kerr, B. · Kinning, E. · Mansour, S. · Hennekam, R.C. · Hout, A.H. van der · Cormier-Daire, V. · Lund, A.M. · Goodwin, L. · Mégarbané, A. · Lees, M. · Betz, R.C. · Tobias, E.S. · Coucke, P. · Mortier, G.R.
Source:American Journal of Medical Genetics, Part C: Seminars in Medical Genetics, 3, 160 C, 205-216
Identifier: 462855
doi: doi:10.1002/ajmg.c.31332
Keywords: Health · COL2A1 · Growth · Spondylo-epiphyseal dysplasia congenita · arginine · asparagine · cysteine · glycine · valine · adult · adulthood · amino acid substitution · amino terminal sequence · anthropometric parameters · article · carboxy terminal sequence · child · codon · Col2a1 gene · female · gene · gene mutation · growth curve · human · major clinical study · male · nucleotide sequence · preschool child · priority journal · spondyloepiphyseal dysplasia · Healthy for Life · Healthy Living · Human · LS - Life Style · BSS - Behavioural and Societal Sciences


From data collected via a large international collaborative study, we have constructed a growth chart for patients with molecularly confirmed congenital spondylo-epiphyseal dysplasia (SEDC) and other COL2A1 related dysplasias. The growth chart is based on longitudinal height measurements of 79 patients with glycine substitutions in the triple-helical domain of COL2A1. In addition, measurements of 27 patients with other molecular defects, such as arginine to cysteine substitutions, splice mutations, and mutations in the C-terminal propeptide have been plotted on the chart. Height of the patients progressively deviate from that of normal children: compared to normal WHO charts, the mean length/height is -2.6 SD at birth, -4.2 SD at 5 years, and -5.8 SD in adulthood. The mean adult height (male and female combined) of patients with glycine substitutions in the triple-helical region is 138.2cm but there is a large variation. Patients with glycine to cysteine substitutions tend to cluster within the upper part of the chart, while patients with glycine to serine or valine substitutions are situated between +1 SD and -1 SD. Patients with carboxy-terminal glycine substitutions tend to be shorter than patients with amino-terminal substitutions, while patients with splice mutations are relatively tall. However, there are exceptions and specific mutations can have a strong or a relatively mild negative effect on growth. The observation of significant difference in adult height between affected members of the same family indicates that height remains a multifactorial trait even in the presence of a mutation with a strong dominant effect. © 2012 Wiley Periodicals, Inc. Molecular Sequence Numbers: GENBANK: NM_001844; Chemicals/CAS: arginine, 1119-34-2, 15595-35-4, 7004-12-8, 74-79-3; asparagine, 70-47-3, 7006-34-0; cysteine, 4371-52-2, 52-89-1, 52-90-4; glycine, 56-40-6, 6000-43-7, 6000-44-8; valine, 7004-03-7, 72-18-4