Deep clinicopathological phenotyping identifies a previously unrecognized pathogenic EMD splice variant

Exome sequencing (ES) has revolutionized rare disease management, yet only ~25%–30% of patients receive a molecular diagnosis. A limiting factor is the quality of available phenotypic data. Here, we describe how deep clinicopathological phenotyping yielded a molecular diagnosis for a 19‐year‐old pro...

Full description

Saved in:
Bibliographic Details
Published in:Annals of clinical and translational neurology 2021-10, Vol.8 (10), p.2052-2058
Main Authors: Calame, Daniel G., Fatih, Jawid M., Herman, Isabella, Coban‐Akdemir, Zeynep, Du, Haowei, Mitani, Tadahiro, Jhangiani, Shalini N., Marafi, Dana, Gibbs, Richard A., Posey, Jennifer E., Mehta, Vidya P., Mohila, Carrie A., Abid, Farida, Lotze, Timothy E., Pehlivan, Davut, Adesina, Adekunle M., Lupski, James R.
Format: Article
Language:English
Subjects:
Adult
Ankle
Antibodies
Biopsy
Case Study
Exome Sequencing
Genes
Genomes
Genomics
Humans
Laboratories
Male
Membrane Proteins - genetics
Membrane Proteins - metabolism
Muscle, Skeletal - metabolism
Muscular dystrophy
Muscular Dystrophy, Emery-Dreifuss - diagnosis
Muscular Dystrophy, Emery-Dreifuss - genetics
Muscular Dystrophy, Emery-Dreifuss - metabolism
Neuromuscular diseases
Neuropathology
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Proteins
Range of motion
Rare diseases
Software
Stains & staining
Young Adult
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Exome sequencing (ES) has revolutionized rare disease management, yet only ~25%–30% of patients receive a molecular diagnosis. A limiting factor is the quality of available phenotypic data. Here, we describe how deep clinicopathological phenotyping yielded a molecular diagnosis for a 19‐year‐old proband with muscular dystrophy and negative clinical ES. Deep phenotypic analysis identified two critical data points: (1) the absence of emerin protein in muscle biopsy and (2) clinical features consistent with Emery‐Dreifuss muscular dystrophy. Sequencing data analysis uncovered an ultra‐rare, intronic variant in EMD, the gene encoding emerin. The variant, NM_000117.3: c.188‐6A > G, is predicted to impact splicing by in silico tools. This case thus illustrates how better integration of clinicopathologic data into ES analysis can enhance diagnostic yield with implications for clinical practice.
ISSN:2328-9503
2328-9503
DOI:10.1002/acn3.51454