期刊
JOURNAL OF MEDICAL GENETICS
卷 55, 期 7, 页码 449-458出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2017-105110
关键词
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资金
- Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) programme [IAP P7/43-BeMGI]
- BridgeIris [RBC/2013-PFS-EH-11]
- Fonds de la Recherche Scientifique-FNRS
- la Communaute francaise de Wallonie-Bruxelles
- la Lotterie Nationale, Belgium
- la region Haut de France, France
- [CdR: J.0080.16]
Background Oral clefts, that is, clefts of the lip and/ or cleft palate (CL/P), are the most common craniofacial birth defects with an approximate incidence of similar to 1/700. To date, physicians stratify patients with oral clefts into either syndromic CL/P (syCL/P) or non-syndromic CL/P (nsCL/P) depending on whether the CL/P is associated with another anomaly or not. In general, patients with syCL/P follow Mendelian inheritance, while those with nsCL/P have a complex aetiology and, as such, do not adhere to Mendelian inheritance Genome-wide association studies have identified approximately 30 risk loci for nsCL/P, which could explain a small fraction of heritability. Methods To identify variants causing nsCL/P, we conducted whole exome sequencing on 84 individuals with nsCL/P, drawn from multiplex families (n=46). Results We identified rare damaging variants in four genes known to be mutated in syCL/P: TP63 (one family), TBX1 (one family), LRP6 (one family) and GRHL3 (two families), and clinical reassessment confirmed the isolated nature of their CL/P. Conclusion These data demonstrate that patients with CL/P without cardinal signs of a syndrome may still carry a mutation in a gene linked to syCL/P. Rare coding and non-coding variants in syCL/P genes could in part explain the controversial question of 'missing heritability' for nsCL/P. Therefore, gene panels designed for diagnostic testing of syCL/P should be used for patients with nsCL/P, especially when there is at least third-degree family history. This would allow a more precise management, follow-up and genetic counselling. Moreover, stratified cohorts would allow hunting for genetic modifiers.
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