Southampton researchers identify new genetic causes for cleft lip and/or palate

The researchers, led by Professor Ignacio Briceno and team in Colombia, and Professor Andrew Collins and colleagues in Southampton, focussed on using next-generation sequencing technology to understand the genetic causes of these syndromes and involved three participating families from the Operation Smile centre in Bogota.

The study of these families demonstrated that DNA sequencing is invaluable in clinical situations for finding genes which cause genetic syndromes such as those including cleft lip and cleft palate.

Until now it has been incredibly difficult to identify the genetic causes of these syndromes because they are triggered by different gene mutations which often show similar clinical features in patients.

DNA sequencing allows these difficulties to be overcome. It also benefits patients by providing them with a greater understanding of the causes of their condition. In turn this greater understanding leads to improved individual treatment and more reliable risk prediction for other family members.

The development of longer term strategies to reduce the incidence of these conditions depends on a comprehensive understanding of the underlying genetic factors involved in all related conditions.

Individuals from the three families in the study showing syndromic phenotypes including cleft lip and/or palate were exome-sequenced. Exome sequencing considers only the small proportion of the DNA which codes for proteins and is therefore a particularly cost-effective strategy for identifying the genetic causes of syndromic conditions. In each case the sequencing revealed the underlying causal variation confirming or establishing diagnoses.

The findings include very rare and novel variants and provide informative insights into the relationship between genotype and phenotype. These include the molecular diagnosis of an individual with Nager syndrome and a family exhibiting an atypical phenotype with a missense mutation more typically associated with preterm male death.

Professor Andrew Collins of the University of Southampton, , said: “Exome sequencing is invaluable for conditions showing phenotypic or genetic heterogeneity including cleft lip and palate phenotypes where many underlying causal genes have not been identified.

It has been incredibly exciting and rewarding to be part of this discovery which, we hope, will lead to improved treatment and better risk prediction for other families.”