Molecular genetics & genomic medicine · 2023
RNA sequencing resolves novel DYNC2H1 variants causing short-rib thoracic dysplasia type 3: Case report.
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Marshall Aren E, MacDonald Stella K, Liang Yijing, Couse Madeline, Care4Rare Canada Consortium, Boycott Kym M, Richer Julie, Kernohan Kristin D
Аннотация
BACKGROUND: Intronic variants outside the canonical splice site are challenging to interpret and therefore likely represent an underreported cause of human disease. Autosomal recessive variants in DYNC2H1 are associated with short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3), a clinically heterogeneous disease generally presenting with short ribs, shortened tubular bones, narrow thorax and acetabular roof anomalies. We describe a case of SRTD3 with compound heterozygous frameshift and intronic variants and highlight the essential role of RNA sequencing (RNA-Seq) in variant interpretation.
METHODS: Following inconclusive clinical genetic testing identifying a likely pathogenic frameshift variant and an intronic variant of uncertain significance (VUS) in DYNC2H1 in trans, the family enrolled in the Care4Rare Canada research program, where RNA-Seq studies were performed.
RESULTS: The proband presented with post-axial polydactyly of all four limbs, a significantly small chest with a pectus excavatum and anterior flaring of the ribs. RNA-Seq investigations revealed a novel splice junction as a result of the intronic VUS and significantly decreased DYNC2H1 gene expression in the proband.
CONCLUSION: This case demonstrates the diagnostic utility of RNA-Seq for variant interpretation following inconclusive clinical testing, which can ultimately lead to diagnosis for patients with rare disease.
METHODS: Following inconclusive clinical genetic testing identifying a likely pathogenic frameshift variant and an intronic variant of uncertain significance (VUS) in DYNC2H1 in trans, the family enrolled in the Care4Rare Canada research program, where RNA-Seq studies were performed.
RESULTS: The proband presented with post-axial polydactyly of all four limbs, a significantly small chest with a pectus excavatum and anterior flaring of the ribs. RNA-Seq investigations revealed a novel splice junction as a result of the intronic VUS and significantly decreased DYNC2H1 gene expression in the proband.
CONCLUSION: This case demonstrates the diagnostic utility of RNA-Seq for variant interpretation following inconclusive clinical testing, which can ultimately lead to diagnosis for patients with rare disease.