In:
Journal of Medical Genetics, BMJ, Vol. 55, No. 7 ( 2018-07), p. 449-458
Abstract:
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 ~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.
Type of Medium:
Online Resource
ISSN:
0022-2593
,
1468-6244
DOI:
10.1136/jmedgenet-2017-105110
DOI:
10.1136/jmedgenet-2017-105110.supp1
DOI:
10.1136/jmedgenet-2017-105110.supp2
DOI:
10.1136/jmedgenet-2017-105110.supp3
DOI:
10.1136/jmedgenet-2017-105110.supp4
Language:
English
Publisher:
BMJ
Publication Date:
2018
detail.hit.zdb_id:
2009590-9
SSG:
12
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