New disease gene location and high genetic heterogeneity in idiopathic scoliosis

Abstract

International audienceIdiopathic scoliosis is a spine disorder of unknown origin with 1.5-3% prevalence in the general population. Besides the large multifactorial form sample of idiopathic scoliosis, there is a good evidence for the existence of a monogenic subgroup in which the disease is inherited in a dominant manner. However, results from literature suggest a strong heterogeneity in the locations of the mutated genes. Using a high resolution genome-wide scan, we performed linkage analyses in three large multigenerational idiopathic scoliosis families compatible with dominant inheritance including 9 to 12 affected members or obligate carriers. In two of these families, our results suggested intra-familial genetic heterogeneity whereas, in the other, we observed a perfect marker disease co-segregation in two regions at 3q12.1 and 5q13.3. We can state that one of these two locations is a novel idiopathic scoliosis disease gene locus, since the probability of having this perfect co-segregation twice by chance in the genome is very low (p=0.001). Lastly, in all three families studied, linkage to the previously mapped dominant idiopathic scoliosis loci on chromosomes 19p13.3, 17p11.2, 9q34, 17q25 and 18q is unlikely, confirming that there is a high genetic heterogeneity within the subgroup of dominant forms of idiopathic scoliosis

Microarray expression profiling identifies genes with altered expression in Adolescent Idiopathic Scoliosis

“…32 genes were identified as corresponding with previously reported AIS candidate loci (Table 5). Within region 19p13.3 [14], we identified two genes to be up-regulated: MKNK2 and CD70, HCLS1 and COL8A1 genes were down-regulated and F2R, F2RL2 and BHMT2 genes were up-regulated in the chromosomal regions identified by Edery et al [11]. Within locus 1p35 [15], TINAGL1 gene was found downregulated.…”

“…Recently, chromosomal regions on 6, 10 and 18q [10], 17p11.2, 19p13.3, Xq23-26.1, 8q11, 9q31.2-q34.2, 17q25.3-qtel, 12p13.31 and recently 3q12.1 and 5q13.3 [11] have been associated with AIS. Even genome-wide association studies (GWAS) have recently been used to study genetic predisposition for AIS and although polymorphisms associated with AIS have been described in SNTG1 on 8q11.22, ESR1 on 6q25.1, MATN1 on 1p35, CHD7 on 8q12.1, MTNR1B on 11q21-q22 and CHL1 [12], no specific genes or proteins have been identified as players in the development of scoliosis.…”

Functional variants of POC5 identified in patients with idiopathic scoliosis

“…Using the affected-only method in a large multiplex family with 11 affected individuals and 1 obligate carrier (family F2), we previously mapped a causative IS gene to either chromosome 5q13.3 or 3q12.3 (8). To identify the IS disease-causing gene, we refined the candidate regions for family F2 to chromosome 5q13.3: 73,905,694-79,488,191 (NCBI hg19; Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI77262DS1) and chromosome 3q12.3: 95,083,093-107,153,338 (NCBI hg19; data not shown) and performed whole-exome sequencing on 3 affected individuals from this family.…”

“…In some of these cases, transmission of the trait appears to be autosomal dominant. However, the results of genome-wide linkage studies in multiplex families were inconclusive, suggesting that IS is genetically heterogeneous (8)(9)(10). GWAS in case/control samples were recently used to identify candidate loci for IS susceptibility (11)(12)(13); however, functional variants unambiguously causing IS have not yet been identified.…”

Genetics and pathogenesis of idiopathic scoliosis

“…This finding could, however, not be replicated in another subset of families [79]. Edery et al [80] suggested linkage to the regions 3q12.1 and 5q13.3 in a multigenerational family. In a follow-up using exome sequencing of three affected members of this family, a novel rare missense variant in POC5 , a centripolar protein, was discovered.…”