Allelic heterogeneity in inbred populations: The Saudi experience with Alström syndrome as an illustrative example

• Published in: American journal of medical genetics. Part A 2009-04, Vol.149A (4), p.662-665
• Main Authors: Aldahmesh, Mohamed A., Abu‐Safieh, Leen, Khan, Arif O., Al‐Hassnan, Zuhair N., Shaheen, Ranad, Rajab, Mohammed, Monies, Dorota, Meyer, Brian F., Alkuraya, Fowzan S.
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alleles; ALMS1; Base Sequence; Biological and medical sciences; Cardiology. Vascular system; cardiomyopathy; Cardiomyopathy, Dilated - genetics; Child; Child, Preschool; Codon, Nonsense; Consanguinity; DNA - genetics; DNA Mutational Analysis; Female; Frameshift Mutation; Hearing Loss, Sensorineural - genetics; Heart; Heterozygote; Homozygote; Humans; Insulin Resistance - genetics; Intellectual deficiency; Liver Failure - genetics; Male; Medical genetics; Medical sciences; mental retardation; Mutation; Myocarditis. Cardiomyopathies; Obesity - genetics; Proteins - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Renal Insufficiency - genetics; retinal dystrophy; Retinitis Pigmentosa - genetics; Saudi Arabia; Syndrome
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.32753

The increased frequency of rare autosomal recessive conditions in genetically isolated populations is a well‐established phenomenon. This genetic isolation is invoked as an explanation when one particular mutation is the sole or most frequent mutation observed in a given population and is referred to as the founder effect. This trend of allelic homogeneity is contrasted by an opposite trend when the consanguinity factor is in play. Independent of endogamy at the population level, a consanguineous union is sufficient to render homozygous a percentage of the genome that is directly correlated with the degree of consanguinity. Assuming the gene in question has a normal mutation rate, the resulting homozygosity will inevitably include different defective alleles of that gene. By reporting four novel alleles, we use Alström disease to exemplify the interesting observation of allelic heterogeneity for a very rare autosomal recessive disorder in a highly inbred population. While we frequently assume founder effect in inbred populations, this report should serve to remind us of the powerful effect of the consanguinity factor, a common confounding variable among some of those populations. © 2009 Wiley‐Liss, Inc.