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

Benjamin Solomon; Kelly Bear; Adrian Wyllie; Amelia Keaton; Christele Dubourg; Véronique David; Sandra Mercier; Sylvie Odent; Ute Hehr; Aimee Paulussen; Nancy Clegg; Mauricio Delgado; Sherri Bale; Felicitas Lacbawan; Holly Ardinger; Arthur Aylsworth; Ntombenhle Louisa Bhengu; Stephen Braddock; Karen Brookhyser; Barbara Burton; Harald Gaspar; Art Grix; Dafne Horovitz; Erin Kanetzke; Hulya Kayserili; Dorit Lev; Sarah Nikkel; Mary Norton; Richard Roberts; Howard Saal; Bradley Schaefer; Adele Schneider; Erika Smith; Ellen Sowry; Anne Spence; Stavit Shalev; Carlos Steiner; Elizabeth Thompson; Thomas Winder; Joan Balog; Donald Hadley; Nan Zhou; Daniel Pineda-Alvarez; Erich Roessler; Maximilian Muenke

doi:10.1136/jmedgenet-2012-101008

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, *}

* Auteur correspondant

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

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 Genetica Medica

19 Department of Medical Genetics

20 Institute of Medical Genetics

21 Department of Genetics

22 Department of Obstetrics and Gynecology

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.

Type de document :

Article dans une revue

Journal of Medical Genetics, BMJ Publishing Group, 2012, 49 (7), pp.473-9. 〈10.1136/jmedgenet-2012-101008〉

Domaine :

Sciences du Vivant [q-bio] / Biologie du développement

Sciences du Vivant [q-bio] / Génétique

Liste complète des métadonnées

http://www.hal.inserm.fr/inserm-00718148
Contributeur : Hervé De Villemeur <>
Soumis le : lundi 16 juillet 2012 - 13:00:23
Dernière modification le : lundi 8 octobre 2018 - 17:44:07

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

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

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