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Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes

Abstract : 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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https://hal-u-picardie.archives-ouvertes.fr/hal-03598608
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Soumis le : samedi 5 mars 2022 - 15:36:39
Dernière modification le : mercredi 7 septembre 2022 - 03:37:48

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Mirta Basha, Bénédicte Demeer, Nicole Revencu, Raphael Helaers, Stephanie Theys, et al.. Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes. Journal of Medical Genetics, BMJ Publishing Group, 2018, 55 (7), pp.449-458. ⟨10.1136/jmedgenet-2017-105110⟩. ⟨hal-03598608⟩

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