Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis

Abstract

Study Design To test for rare genetic mutations, a cohort of patients with unexplained early onset scoliosis (EOS) was screened using high-density microarray genotyping. A cohort of patients with adolescent idiopathic scoliosis (AIS) was similarly screened, and the results were compared. Summary of background data Patients with scoliosis in infancy or early childhood (EOS) are at high risk for progressive deformity and associated problems including respiratory compromise. EOS is frequently associated with genetic disorders, but many patients present with non-specific clinical features and without an associated diagnosis. We hypothesized that EOS in these patients may be caused by rare genetic mutations detectable by next-generation genomic methods. Methods We ascertained 24 patients with unexplained EOS from pediatric orthopedic clinics. We genotyped them, along with 39 connecting family members, using the Illumina OmniExpress-12 v1.0 beadchip. Resulting genotypes were analyzed for chromosomal changes, specifically copy number variation (CNV) and absence of heterozygosity (AOH). We screened 482 AIS patients and 744 healthy controls, which were similarly genotyped with the same beadchip, for chromosomal changes identified in the EOS cohort. Results Copy number variation (CNV) and absence of heterozygosity (AOH) analyses revealed a genetic diagnosis of chromosome 15q24 microdeletion syndrome in one patient, and maternal uniparental disomy of chromosome 14 in a second patient. Prior genetic testing and clinical evaluations had been negative in both cases. A large novel chromosome 10 deletion was likely causal in a third EOS patient. These mutations identified in the EOS patients were absent in AIS patients and controls, and thus not associated with AIS or found in asymptomatic individuals. Conclusions Our data underscore the utility of updated genetic evaluations including high-density microarray-based genotyping and other “next-generation” methods in patients with unexplained EOS, even where prior genetic studies were negative. These data also suggest the intriguing possibility that other mutations detectable by whole genome sequencing, as well as epigenetic effects, await discovery in the EOS population.

Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders

“…Studies were admitted to this paper's analysis when the following criteria were met: (1) the study detailed parent of origin data for one of the 38 eligible NAHR-mediated loci as designated by Coe et al [7], (2) the authors of the study interrogated the entire canonical CNV interval to confirm the presence of a deletion or duplication in the patients, (3) the authors determined the investigated CNVs were de novo, and (4) the study clearly treated monozygotic twins as one meiotic event and not two (Additional file 1: Supplemental Methods, Additional file 2: Table S1, and Additional file 3: Table S2). The literature search led to a manual review of 1268 papers, out of which we identified 77 manuscripts across 24 loci with suitable data for analysis: 1q21.1 [35][36][37][38][39], 1q21.1 TAR [40], 2q13 [37], 3q29 [37][38][39][40][41][42], 5q35 [31,32], 7q11.23 [24,40,[43][44][45][46][47][48][49][50][51][52][53][54], 8p23.1 [55,56], 11q13.2q13.4 [57], 15q13.3 [38,40,58], 15q24 (AC, AD, BD, and BE intervals) [59][60]…”

“…Data are consolidated by locus. BED coordinates correspond to hg38 (LiftOver from hg18 coordinates in Coe et al[7])intervals)[59][60][61][62][63][64], 15q25.2[65][66][67],16p11.2[26,37,40,[68][69][70], distal 16p11.2[37,38,70], 16p11.2p12.1[71], 16p31.11[37], 17p11.2[72][73][74][75][76], 17q11.2[28,29,77], 17q12[37,38,78], 17q21.31[19,25,67,[79][80][81][82][83][84], 17q23.1q23.2[69,85] and 22q11.2[30,43,53,[86][87][88][89]…”

Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis

“…The 16p11.2 microdeletion was found to be associated with CS [13], and recent studies demonstrated that a compound inheritance of a TBX6-containing 16p11.2 microdeletion and a TBX6 mutation or hypomorphic haplotype accounted for 5-10% of patients with CS in different populations [14][15][16][17]. Additional CNVs, including 10q24.31, 17p11.2, 20p11, 22q11.2, and a few other regions, were respectively reported in individual patients with CVMs [18,19]. Besides 16p11.2 microdeletion, it is unknown whether other CNVs are prevalent in CS.…”

Refining critical regions in 15q24 microdeletion syndrome pertaining to autism

“…in 2007, with many more cases now reported and the prevalence assessed to be 3:10,000-4:10,000 ([Klopocki et al, 2008;Marshall et al, 2008;Kiholm Lund, et al, 2008;Andrieux et al, 2009;El-hattab et al, 2009;Masurel-Paulet et al, 2009, Van Esch et al, 2009El-Hattab et al, 2010;McInnes et al, 2010;Ng et al, 2011;Brun et al, 2012;Mefford et al, 2012aMefford et al, , 2012bNarumi et al, 2012;Gao et al, 2014;Samuelsson et al, 2015;Siu etal.,2016;Palazon-Bru et al, 2016;Romano et al, 2017;Ahram et al, 2017;Huynh et al,2017;Dai et al, 2017;Wang et al, 2019]). Most of 15q24 deletions were found between 1.7 and 6.1 Mb in size with breakpoints localized to the clusters of five low copy regions (LCRs) from centromere to telomere, which were identified and designated as LCR15q24A (BP4), B High anterior hairline 5 (11.1) 4 (8.9) 3 (6.7) 1 (2.2)…”