Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

Marchant, RG; Bryen, SJ; Bahlo, M; Cairns, A; Chao, KR; Corbett, A; Davis, MR; Ganesh, VS; Ghaoui, R; Jones, KJ; Kornberg, AJ; Lek, M; Liang, C; MacArthur, DG; Oates, EC; O&#39;Donnell-Luria, A; O&#39;Grady, GL; Osei-Owusu, IA; Rafehi, H; Reddel, SW; Roxburgh, RH; Ryan, MM; Sandaradura, SA; Scott, LW; Valkanas, E; Weisburd, B; Young, H; Evesson, FJ; Waddell, LB; Cooper, ST

Author(s): Marchant, RG; Bryen, SJ; Bahlo, M; Cairns, A; Chao, KR; Corbett, A; Davis, MR; Ganesh, VS; Ghaoui, R; Jones, KJ; Kornberg, AJ; Lek, M; Liang, C; MacArthur, DG; Oates, EC; O'Donnell-Luria, A; O'Grady, GL; Osei-Owusu, IA; Rafehi, H; Reddel, SW; Roxburgh, RH; Ryan, MM; Sandaradura, SA; Scott, LW; Valkanas, E; Weisburd, B; Young, H; Evesson, FJ; Waddell, LB; Cooper, ST;
Details: Publication Year 2024-03-27,Volume 11,Issue #5,Page 1250-1266
Journal Title: Annals of Clinical and Translational Neurology
Abstract: OBJECTIVE: Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence-based recommendations for their integration into practice. METHODS: In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research-led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required. RESULTS: Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice-altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene-panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today. INTERPRETATION: Our results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post-exome auxiliary investigations extended our diagnostic yield by 81% overall (34-62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing.
Publisher: Wiley
Keywords: Humans; *Neuromuscular Diseases/genetics/diagnosis; *Exome Sequencing; Male; Female; Adult; Sequence Analysis, RNA/methods; Child; Adolescent; Exome/genetics; Middle Aged; Young Adult; Child, Preschool; High-Throughput Nucleotide Sequencing; Infant; Genetic Testing/methods
Research Division(s): Population Health And Immunity
PubMed ID: 38544359
Publisher's Version: https://doi.org/10.1002/acn3.52041
Open Access at Publisher's Site: https://doi.org/10.1002/acn3.52041
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-04-08 12:14:51

Last Modified: 2024-06-28 03:08:40