Deep clinicopathological phenotyping identifies a previously unrecognized pathogenic EMD splice variant.

Area of Science:

• Genomics
• Rare Diseases
• Clinical Pathology

Background:

• Exome sequencing (ES) has transformed rare disease diagnosis, but diagnostic rates remain suboptimal (~25%-30%).
• Incomplete or inaccurate phenotypic data is a significant barrier to achieving molecular diagnoses via ES.
• Enhanced integration of detailed clinical and pathological information is crucial for improving diagnostic yield.

Observation:

• A 19-year-old proband with muscular dystrophy, initially undiagnosed by clinical exome sequencing, was investigated.
• Deep clinicopathological phenotyping revealed the absence of emerin protein in muscle biopsy and features consistent with Emery-Dreifuss muscular dystrophy.
• This detailed phenotyping provided critical insights beyond standard clinical data.

Findings:

• Analysis of sequencing data, guided by phenotyping, identified an ultra-rare, intronic variant (NM_000117.3: c.188-6A>G) in the EMD gene.
• In silico tools predicted this EMD variant significantly impacts RNA splicing.
• The identified variant provides a molecular explanation for the patient's condition.

Implications:

• This case highlights the critical role of integrating deep clinicopathological phenotyping with exome sequencing analysis.
• Improved data integration can significantly enhance the diagnostic yield of exome sequencing for rare genetic disorders.
• These findings have direct implications for refining diagnostic strategies in clinical practice for rare diseases.