Study Design.

Genome-wide linkage surveys in large multiplex families with apparent inherited idiopathic scoliosis.

Objective.

To identify chromosomal loci encoding genes involved in susceptibility to idiopathic scoliosis by positional cloning.

Summary of Background Data.

Although the inheritance of idiopathic scoliosis most often exhibits a complex pattern, autosomal dominant inheritance can be identified in some families. Families exhibiting such an inheritance pattern present an opportunity to identify the predisposing gene (s) by positional cloning.

Methods.

Probands having clinically relevant idiopathic scoliosis (50 Cobb angle) from large multiplex families were identified. A curve of 15, made from standing posteroanterior radiographs, was required for a positive diagnosis. A genome-wide search in one large family (seven affected members) was conducted with 385 polymorphic microsatellite markers spaced at an approximate 10-cM resolution. Hot spots identified in this family were subsequently tested in a second large kindred.

Results.

Maximum evidence of allele-sharing in affected individuals from the first family was detected for three loci on chromosomes 6p, distal 10q, and 18q with nonparametric lod scores of 1.42 (P= 0.020), 1.60 (P= 0.019), and 8.26 (P= 0.002), respectively. Evidence of allele-sharing was also detected in the second family at distal chromosome 10q (nonparametric lod score= 2.02; P= 0.033).

Conclusions.

These data indicate a limited number of genetic loci predisposing to idiopathic scoliosis.

Is idiopathic scoliosis (IS) a genetic disorder? A familial tendency has long been recognized in the clinics. Clinical studies indicate that approximately one fourth of the total scoliosis cases and one third of IS cases are familial, 21 and twin studies show that the concordance of monozygotic twins is greater than that of dizygotic twins, confirming a genetic basis to IS. 12 However, the inheritance pattern of familial IS is not clear cut. A review of existing literature shows that the disorder demonstrates many of the characteristics of a complex trait, 7, 8, 18, 22 yet autosomal dominant inheritance patterns have been suggested as well. 2, 9 In more formal segregation analyses, conflicting data have been presented in which the same collection of families produced evidence of a major (autosomal dominant) gene effect in one study 1 but indicated multifactorial inheritance in another. 6 The general interpretation of this seemingly confusing evidence is that IS exhibits a complex pattern of inheritance in most cases, but, more rarely, it appears to be inherited in an autosomal dominant fashion. 6