Bardet Biedl syndrome in South Africa: A single founder mutation

Abstract

Background. Bardet Biedl syndrome (BBS) is a multisystem disorder characterised by obesity, polydactyly, intellectual disability and loss of vision due to a progressive retinopathy. Although typically a highly heterogeneous autosomal recessive disease, homozygosity for single mutation in BBS 10 has been identified in a significant number of affected individuals tested in South Africa (SA). Objectives. To delineate the ethnic distribution and clinical phenotype in a cohort of SA BBS patients with the K243IfsX15 mutation in BBS 10 and discuss the implications for genetic testing of and counselling for this disorder in SA.Method. This was a descriptive cross-sectional study collating clinical and laboratory data retrospectively in a genetically homogenous subgroup of BBS patients from SA. Results. A total of 76 patients from 74 families were tested. Homozygosity for the K243IfsX15 BBS 10 mutation was found in 50 families (67%) and heterozygosity for the same mutation in an additional two affected individuals. With the exception of one patient of mixed ancestry, all were black South Africans from different language groups. This is in keeping with the observation that BBS is more common in this ethnic group compared with white and coloured patients in SA, first made by Prof. Beighton nearly 3 decades ago. A subset of 15 patients available for detailed phenotyping confirmed consistency with well-described features of the disorder, with some overlap with other ciliopathies. The onset of visual impairment was early in our cohort, before the age of 8 years, cognitive impairment was significant, and renal and cardiac abnormalities were infrequently encountered. Conclusion. The high frequency of homozygosity for a single mutation in an ethnic subset of the SA population is strongly suggestive of a founder effect. This has allowed establishment of a diagnostic test with a high yield in our local population. Better understanding of the phenotype will improve earlier recognition of the disorder to allow for appropriate intervention. Testing can confirm but not negate a clinical diagnosis, and can permit carrier and prenatal testing in informative families.

Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

“…It is of note that, even if multiethnic, our cohort was mainly composed of pedigrees from Caucasian descent. This strategy might be adapted to ethnic background if applied in non‐European patients, given the fact that the gene distribution may vary from one population to another or be subject to founder effects …”

“…This strategy might be adapted to ethnic background if applied in non-European patients, given the fact that the gene distribution may vary from one population to another 47,[50][51][52] or be subject to founder effects. 53 Taking into account both the US and the autopsy data, postaxial polydactyly and renal anomalies were the most prevalent signs of BBS. Hydrometrocolpos, an evocative sign of MKKS/BBS, was present only in three fetuses.…”

Bardet–Biedl syndrome: expect the unexpected, suspect the unsuspected

“…3 Numerous additional nondiagnostic features are described, although the association may be unreliable in some. [2][3][4][5]9,12,13,15,[22][23][24]…”

“…2,3,9,12,13,23 Frequencies of polydactyly/ brachydactyly/syndactyly vary widely in different BBS populations but are common. 3,5,9,15 These features are associated with several other syndromes which have craniofacial or airway abnormalities, especially bifid epiglottis, 18,28,[39][40][41] and if present in an undiagnosed child should alert the anaesthetist to an underlying syndrome with potential airway problems.…”

“…13,14 Craniofacial and airway abnormalities are not considered diagnostic in BBS, 3 yet there is increasing recognition of the pattern, frequency, associated morbidity and anaesthetic challenges. 9,12,13,15 We describe the unexpected finding of a bifid epiglottis and anterior laryngeal web in a 15-month-old child with BBS who developed upper airway obstruction (UAO) and stridor during anaesthesia for club foot correction. A clinical review of BBS is provided, highlighting features that may occur across a spectrum of syndromes and have implications for airway management.…”