A Population-Based Study of Autosomal-Recessive Disease-Causing Mutations in a Founder Population

Abstract

The decreasing cost of whole-genome and whole-exome sequencing has resulted in a renaissance for identifying Mendelian disease mutations, and for the first time it is possible to survey the distribution and characteristics of these mutations in large population samples. We conducted carrier screening for all autosomal-recessive (AR) mutations known to be present in members of a founder population and revealed surprisingly high carrier frequencies for many of these mutations. By utilizing the rich demographic, genetic, and phenotypic data available on these subjects and simulations in the exact pedigree that these individuals belong to, we show that the majority of mutations were most likely introduced into the population by a single founder and then drifted to the high carrier frequencies observed. We further show that although there is an increased incidence of AR diseases overall, the mean carrier burden is likely to be lower in the Hutterites than in the general population. Finally, on the basis of simulations, we predict the presence of 30 or more undiscovered recessive mutations among these subjects, and this would at least double the number of AR diseases that have been reported in this isolated population.

Disclosure of Genetic Research Results to Members of a Founder Population

“…These studies revealed surprisingly high carrier frequencies for some diseases that had not been recognized as common in the Hutterites (e.g., 1 in 8 Hutterites are carriers for the mutation causing spinal muscular atrophy, [SMA; OMIM 253400]; Chong et al, 2011; Chong et al, 2012). The high participation rate in the study offering CF carrier results indicated that many Hutterites were interested in learning about their carrier status for a monogenic disease.…”

“…An invitational flyer described the program and included the title of each talk that would be presented. At the Town Hall we distributed a brochure (Online Resource 3) that described the 14 genetic diseases and their carrier frequencies in the Hutterites (Chong et al, 2012; Gerull et al, 2013) and reviewed autosomal recessive inheritance. The format of the Town Hall consisted of three half-hour presentations.…”

“…The letter emphasizes that these are research results and should be clinically confirmed before being used to guide medical care or decision making. The letter also provides interpretation of all results, reviews autosomal recessive inheritance and risks, and emphasizes that the participant could still be a carrier for mutations causing any of the remaining autosomal recessive diseases that are segregating in this population (Armistead et al, 2009; Beaulieu et al, 2013; Bogershausen et al, 2013; Boycott et al, 2010; Boycott et al, 2008; Chong et al, 2012; Wiltshire, Hegele, Innes, & Brownell, 2013). The letter invites recipients to contact us by mail or phone with further questions and offers our assistance in arranging clinical confirmation of results.…”

A novel mutation inKIAA0196: identification of a gene involved in Ritscher–Schinzel/3C syndrome in a First Nations cohort

“…Similar carrier frequencies due to founder mutations are not uncommon in genetic and geographic isolates. For example, the Limb Girdle Muscular Dystrophy mutation in TRIM32 (p.Asp487Asn) has an estimated frequency of 1 in 6.5 in Hutterite individuals 16. None of 212 chromosomes from 106 random Caucasian individuals carried the c.3335+8A>G mutation.…”

Plant Sterols, Stanols, and Sitosterolemia

“…Increased PS intakes have been speculated in the development of many risk factors associated with sitosterolemia. Aside from the basic presentation of xanthomas and premature atherosclerosis in sitosterolemic patients (18, 65, 72), new clinical features such as macrothrombocytopenia (giant platelets with reduced count), hemolytic anemia, splenomegaly and arthritis have been associated with this rare disease (24, 33, 68; Table 1). …”