Deciphering the mutational signature of congenital limb malformations

Abstract

Congenital limb malformations (CLMs) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study was to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely pathogenic single-nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified RPL9 and UBA2 as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p = 0.012) or more than one limb affected (p = 0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes.

Identification of Novel FBN2 Variants in a Cohort of Congenital Contractural Arachnodactyly

“…We included ten families diagnosed with CCA and carrying pathogenic FBN2 variant from Beijing Jishuitan Hospital and Peking Union Medical College Hospital based on the D eciphering disorders I nvolving S coliosis and CO morbidities (DISCO) study ( http://www.discostudy.org/ ) ( Tian et al, 2020 ; Sun et al, 2021 ). Informed consent was obtained from all patients or their guardians.…”

“…As a part of DISCO study, peripheral blood DNA from probands and available familial members were prepared into Illumina paired-end libraries and underwent whole-exome capture with the Agilent V5, followed by sequencing on the Illumina HiSeq 4,000 platform (Illumina, San Diego, CA, United States). In-house-developed P eking U nion M edical college hospital P ipeline (PUMP) was used for variant calling and annotation ( Zhao et al, 2020 ; Chen et al, 2021 ; Sun et al, 2021 ).…”

Phen2Disease: A Phenotype-driven Semantic Similarity-based Integrated Model for Disease and Gene Prioritization

“…The cases came from five types of resources [34][35][36][37][38], such as the American Journal of Human Genetics Article, Columbia University Medical Center, and the Department of Genomic Diagnostics at the Children's Hospital of Philadelphia. For Cohorts 3-5, we used the same data cohort as Chen et al [30] group [42][43][44]. For Cohort 6, we used the same data cohort as Yuan et al [45].…”

Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability

“…During the past decade, elucidation of the molecular etiology of CLM has been facilitated by advances in high-throughput family-based genomics, rare variant allele studies, computational tools, and population variation studies, driving the molecular diagnostic “solved rate” of a random CLM-related cohort to be reported with a range of 10%–35% in different populations. 7 , 8 , 9 , 10 , 11 To date, more than 150 “disease trait genes or loci” have been attributed to CLM in affected individuals and families. A diverse mutational landscape comprised of single-nucleotide variant (SNV) alleles, small insertion or deletion (indel) events, simple sequence repeat expansions, and locus copy number variant (CNV) alleles involving coding or non-coding regulatory regions has been elucidated.…”

“…A diverse mutational landscape comprised of single-nucleotide variant (SNV) alleles, small insertion or deletion (indel) events, simple sequence repeat expansions, and locus copy number variant (CNV) alleles involving coding or non-coding regulatory regions has been elucidated. 8 , 12 , 13 …”