From karyotypes to precision genomics in 9p deletion and duplication syndromes

Abstract

While 9p deletion and duplication syndromes have been studied for several years, small sample sizes and minimal high-resolution data have limited a comprehensive delineation of genotypic and phenotypic characteristics. In this study, we examined genetic data from 719 individuals in the worldwide 9p Network Cohort: a cohort seven to nine times larger than any previous study of 9p. Most breakpoints occur in bands 9p22 and 9p24, accounting for 35% and 38% of all breakpoints, respectively. Bands 9p11 and 9p12 have the fewest breakpoints, with each accounting for 0.6% of all breakpoints. The most common phenotype in 9p deletion and duplication syndromes is developmental delay, and we identified eight known neurodevelopmental disorder genes in 9p22 and 9p24. Since it has been previously reported that some individuals have a secondary structural variant related to the 9p variant, we examined our cohort for these variants and found 97 events. The top secondary variant involved 9q in 14 individuals (1.9%), including ring chromosomes and inversions. We identified a gender bias with significant enrichment for females (p = 0.0006) that may arise from a sex reversal in some individuals with 9p deletions. Genes on 9p were characterized regarding function, constraint metrics, and protein-protein interactions, resulting in a prioritized set of genes for further study. Finally, we achieved precision genomics in one child with a complex 9p structural variation using modern genomic technologies, demonstrating that long-read sequencing will be integral for some cases. Our study is the largest ever on 9p-related syndromes and provides key insights into genetic factors involved in these syndromes.

HAT:de novovariant calling for highly accurate short-read and long-read sequencing data

“…Short-read WGS data were assessed from our previous publication in 4,216 trios from the Simons Simplex Collection (Ng, et al, 2022). Highly accurate long-read WGS data for four trios were assessed from our previous publications (Mehinovic, et al, 2022; Sams, et al, 2022).…”

Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy characterized by long‐read sequencing

“…Long-read sequencing is promising for the objective of precision genomics. We previously defined precision genomics as "determining all possible relevant genomic variation within an individual to the precise nucleotide" (Sams et al, 2022) and emphasized the importance of precision genomics in the framework of precision medicine (Sams et al, 2022). Furthermore, family-based studies have been highly successful in identifying de novo variants and long-read sequencing coupled with family-based analyses should prove especially fruitful for gene discovery in families with no known genetic cause.…”

Male with Deletion 9p Terminal Syndrome with Sexual Development Disorder

“…(Hou et al, 2016;Huret et al, 1988) Around two thirds of 9p deletion cases are de novo or sporadic, due to a deficient paternal or maternal meiosis and the remaining third is the result of unbalanced rearrangements inherited by either parent carrying a balanced translocation. (Van Ravenswaaij et al, 2005) In the literature there are studies in which the size of deletion is variable and even with several attempts to reach a critical region between 4-6 Mb (Kawara et al, 2006;Sams et al, 2022), there is no region yet recognized for this syndrome. Most of the patients have either a pure terminal deletion that involves the short arm of chromosome 9 or big unbalanced chromosomic rearrangements up to 18.9 Mb (Ng et al, 2020).…”

“…Therefore, the genotype-phenotype correlation could be associated to the break-point position of the deletion 9p region, which could be proximal, interstitial, distal or pericentric, since chromosome 9 involves several genes associated with cerebral, embryologic and sexual development as well as for cranial morphology, signaling networks associated to the bone morphogenic protein (BMP), transcription factors, initiation of transcription, etc. (Sams et al, 2022) (Figure 1). This article presents a case of 9p terminal deletion with different clinical features to the consensus phenotype of 9p deletion syndrome, whose first approach was through the disorder of sexual development (DSD).…”