IVIC syndrome Is caused by a c.2607delA mutation in the SALL4 locus

Abstract

The IVIC syndrome described in 1980 in a large Venezuelan family, is an autosomal dominant condition characterized by upper limbs anomalies (radial ray defects, carpal bones fusion), extraocular motor disturbances, congenital bilateral non‐progressive mixed hearing loss; other less consistent malformations include heart involvement, mild thrombocytopenia and leukocytosis (before age 50), shoulder girdle hypoplasia, imperforate anus, kidney malrotation or rectovaginal fistula. Since 2002, mutations in the SALL4 locus have been reported producing phenotypic features quite similar to those in IVIC syndrome; this gene was thus proposed as a candidate for the condition. A segregation analysis of four SNPs in exon 2 (c.1520T > G, c.1860A > G, c.2037C > T, and c.2392A > C) was carried out in 14 affected and in 15 normal family members. Haplotype T;A;C;A was found to always segregate with the disease. Sequencing the whole coding regions revealed one heterozygous base deletion in exon 3 (c.2607delA) causing a premature stop signal 44 codons downstream (p.Q869fsX44) which segregates with the phenotype, being absent in controls. The large number of affected individuals presumably carrying the same mutation (n = 26) with quite different degrees of involvement allowed a discussion about possible mechanisms for the SALL4 action. The finding of a SALL4 mutation in a family with such a wide pleiotropic spectrum proves that at least Okihiro, acro‐renal‐ocular and IVIC syndromes are allelic entities.