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Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.

Benjamin Solomon 1 Kelly Bear 1, 2 Adrian Wyllie 1 Amelia Keaton 1 Christele Dubourg 3 Véronique David 3 Sandra Mercier 3, 4 Sylvie Odent 3 Ute Hehr 5 Aimee Paulussen 6 Nancy Clegg 7 Mauricio Delgado 7 Sherri Bale 8 Felicitas Lacbawan 9 Holly Ardinger 10 Arthur Aylsworth 11 Ntombenhle Louisa Bhengu 12 Stephen Braddock 13 Karen Brookhyser 14 Barbara Burton 15, 16 Harald Gaspar 17 Art Grix 14 Dafne Horovitz 18 Erin Kanetzke 13 Hulya Kayserili 19 Dorit Lev 20 Sarah Nikkel 21 Mary Norton 22 Richard Roberts 23 Howard Saal 24 Bradley Schaefer 25 Adele Schneider 26 Erika Smith 21 Ellen Sowry 27 Anne Spence 28 Stavit Shalev 29, 30 Carlos Steiner 31 Elizabeth Thompson 32 Thomas Winder 33 Joan Balog 1 Donald Hadley 1 Nan Zhou 1 Daniel Pineda-Alvarez 1 Erich Roessler 1 Maximilian Muenke 1, *
* Corresponding author
1 Cancer Genetics Branch
2 Department of Pediatrics
3 IGDR - Institut de Génétique et Développement de Rennes
4 Service de génétique clinique [Rennes]
5 Department of Human Genetics
6 Department of Clinical Genetics
7 Department of Neurology
8 GeneDx [Gaithersburg, MD, USA]
9 Molecular Genetics Pathology
10 Department of Pediatrics
11 Department of Pediatrics
12 Department of Human Genetics
13 Department of Pediatrics
14 Genetics Department
15 Department of Pediatrics
16 Division of Genetics, Birth Defects and Metabolism
17 Human Genetics Institute
18 Centro de Genética Médica [Rio de Janeiro]
19 Department of Medical Genetics
20 Institute of Medical Genetics
21 Department of Genetics
22 Department of Obstetrics and Gynecology [Stanford]
23 Genetics and Prenatal Diagnostic Center
24 Department of Pediatrics
25 Division of Medical Genetics
26 Genetics Division
27 Division of Medical Genetics
28 Department of Pediatrics
29 Genetics Institute
30 Rappaport faculty of Medicine
31 Department of Medical Genetics
32 Clinical Genetics Unit
33 Prevention Genetics
Abstract : Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. Conclusions SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.
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https://www.hal.inserm.fr/inserm-00718148
Contributor : Hervé de Villemeur <>
Submitted on : Monday, July 16, 2012 - 1:00:23 PM
Last modification on : Monday, April 19, 2021 - 10:20:20 AM

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INSERM | CNRS | UNIV-RENNES1 | IGDR | BIOSIT | UR1-UFR-SVE | UNIV-RENNES | RIIP

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Benjamin Solomon, Kelly Bear, Adrian Wyllie, Amelia Keaton, Christele Dubourg, et al.. Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.. Journal of Medical Genetics, BMJ Publishing Group, 2012, 49 (7), pp.473-9. ⟨10.1136/jmedgenet-2012-101008⟩. ⟨inserm-00718148⟩

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