Reanalysis of RNA sequencing data ends diagnostic odyssey and expands the phenotypic spectrum of congenital titinopathy.

Autor: McNamee L; UNC-Greensboro Genetic Counseling Program, Greensboro, North Carolina, USA., Schoch K; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA., Huang A; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.; Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA., Lee H; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA., Wang LK; Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA., Smith EC; Division of Pediatric Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA., Lark RK; Department of Orthopedics, Duke University Medical Center, Durham, North Carolina, USA., Buckley AF; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., Jobanputra V; Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.; New York Genome Center, New York, New York, USA., Nelson SF; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.; Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.; Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA., Shashi V; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Nov; Vol. 194 (11), pp. e63798. Date of Electronic Publication: 2024 Jun 24.
DOI: 10.1002/ajmg.a.63798
Abstrakt: Although next-generation sequencing has enabled diagnoses for many patients with Mendelian disorders, the majority remain undiagnosed. Here, we present a sibling pair who were clinically diagnosed with Escobar syndrome, however targeted gene testing was negative. Exome sequencing (ES), and later genome sequencing (GS), revealed compound heterozygous TTN variants in both siblings, a maternally inherited frameshift variant [(NM_133378.4):c.36812del; p.(Asp12271Valfs*10)], and a paternally inherited missense variant [(NM_133378.4):c.12322G > A; p.(Asp4108Asn)]. This result was considered nondiagnostic due to poor clinical fit and limited pathogenicity evidence for the missense variant of uncertain significance (VUS). Following initial nondiagnostic RNA sequencing (RNAseq) on muscle and further pursuit of other variants detected on the ES/GS, a reanalysis of noncanonical splice sites in the muscle transcriptome identified an out-of-frame exon retraction in TTN, near the known VUS. Interim literature included reports of patients with similar TTN variants who had phenotypic concordance with the siblings, and a diagnosis of a congenital titinopathy was given 4 years after the TTN variants had been initially reported. This report highlights the value of reanalysis of RNAseq with a different approach, expands the phenotypic spectrum of congenital titinopathy and also illustrates how a perceived phenotypic mismatch, and failure to consider known variants, can result in a prolongation of the diagnostic journey.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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