title: WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.
abstract: Most cases of juvenile-onset diabetes (JOD) are diagnosed as type 1 diabetes (T1D), for which genetic studies conducted in outbred Caucasian populations support the concept of multifactorial inheritance. However, this view may be partly challenged in particular population settings. In view of the suggestive evidence for a high prevalence of Wolfram syndrome (WFS) in Lebanon, the phenotypic variability associated with WFS1 mutations, and the high consanguinity rate in Lebanon, we aimed to evaluate the contribution of WFS1 mutations as monogenic determinants to JOD in Lebanon. We performed a family-based genetic study, with linkage analysis followed by systematic mutation screening of WFS1 exons in all JOD probands. The study population consisted of an unbiased recruitment of all juvenile-onset insulin-dependent diabetic patients from a specialized diabetes pediatric clinic in Beirut, Lebanon. Homozygous or compound heterozygous WFS1 mutations were found in 22 of the 399 JOD probands (5.5%), resulting in WFS (17 probands) or in non-syndromic non-autoimmune diabetes mellitus (DM, five probands). These accounted for 12.1% (21/174) of probands in consanguineous families, compared with 0.4% (1/225) in non-consanguineous families. Of the 38 patients identified with homozygous or compound heterozygous WFS1 mutations, 11 (29%) had non-syndromic DM, all of whom carried a particular WFS1 mutation, WFS1(LIB), encoding a protein with an extended C-terminal domain. This mutation resulted in a delayed onset or absence of extrapancreatic features. These results underscore the major impact of population-specific factors, such as population-specific mutations and founder effects, and family structure in the genetic determinism of JOD.
authors.affiliation: Lebanese American University, School of Medicine, Chouran, Beirut 1102 2801, Lebanon.
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Zalloua
authors.forename: Sami T
authors.initials: ST
authors.lastname: Azar
authors.forename: Marc
authors.initials: M
authors.lastname: Delépine
authors.forename: Nadine J
authors.initials: NJ
authors.lastname: Makhoul
authors.forename: Hervé
authors.initials: H
authors.lastname: Blanc
authors.forename: May
authors.initials: M
authors.lastname: Sanyoura
authors.forename: Anne
authors.initials: A
authors.lastname: Lavergne
authors.forename: Karmen
authors.initials: K
authors.lastname: Stankov
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lemainque
authors.forename: Patrick
authors.initials: P
authors.lastname: Baz
authors.forename: Cécile
authors.initials: C
authors.lastname: Julier
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000096:biosynthesis; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005091:Exons / Q000235:genetics; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007861:Lebanon / Q000453:epidemiology; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D015995:Prevalence; D013577:Syndrome; D014929:Wolfram Syndrome / Q000453:epidemiology / Q000235:genetics; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D005819:Genetic Markers; D008565:Membrane Proteins; C114987:wolframin protein