2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-A novel deep intronic variant in <em>DYNC2H1</em> characterized through exome reanalysis in a neonate with short-rib thoracic dysplasia type III

A novel deep intronic variant in DYNC2H1 characterized through exome reanalysis in a neonate with short-rib thoracic dysplasia type III

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Researchers from Indiana University School of Medicine have identified a novel deep intronic variant in the DYNC2H1 gene in a neonate with short-rib thoracic dysplasia type III (SRTD). The neonate was admitted to the Neonatal Intensive Care Unit (NICU) due to respiratory distress caused by a small, narrow chest. Exome sequencing revealed a maternally-inherited likely pathogenic variant in DYNC2H1, but no variant was found on the paternal allele.<br /><br />The researchers performed RNA sequencing and quantitative droplet digital PCR (ddPCR) to assess the impact of the variant on splicing and mRNA levels, respectively. The results indicated that the deep intronic variant led to abnormal intron retention and a 74% reduction in the expression of DYNC2H1.<br /><br />The identification of the deep intronic variant was possible through the reanalysis of the exome sequencing data. Deep-intronic splice variants are typically not detected in routine diagnostics, highlighting the potential of reanalysis in uncovering previously unidentified variants.<br /><br />The researchers reclassified the intronic variant as likely pathogenic, allowing the patient to receive a definitive genetic diagnosis and expanding the understanding of SRTD genotype. The collaboration between the NICU and the Undiagnosed Rare Disease Clinic at Indiana University School of Medicine resolved the family's diagnostic odyssey and provided the opportunity for prenatal diagnosis of SRTD in the mother's current pregnancy.<br /><br />Overall, this study demonstrates the importance of reanalysis in identifying deep intronic variants and highlights the clinical relevance of studying patient-derived fibroblasts in uncovering clinically relevant alterations missed by other methods.

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Presenting Author - Muqsit B. Buchh, BS; Co-Author - Patrick J. Gillespie, PhD; Co-Author - Kayla Treat, MS, CGC; Co-Author - Marco Abreu, MS; Co-Author - Tae-Hwi L. Schwantes-An, PhD, MS; Co-Author - Benjamin M. Helm, MS, CGC; Co-Author - Fang Fang, PhD; Co-Author - Xaoling Xuei, MS, PhD; Co-Author - Lili R. Mantcheva, MPH, CCRP; Co-Author - Kristen Suhrie, MD; Co-Author - Brett H. Graham, MD, PhD; Co-Author - Erin E. Conboy, MD, FACMG; Co-Author - Francesco Vetrini, PhD, FACMG;

Meta Tag

Biochemical genetics

Bone/Joint Abnormalities

Congenital Anomaly

Databases

Exome sequencing

Genetic Testing

Genitourinary malformations

Genome sequencing

Genotype-Phenotype Correlations

Inheritance Patterns

Malformation

Microarray

Musculoskeletal system

Phenotype

Pulmonary/respiratory malformations

Respiratory System

Sequencing

Variant Detection

Co-Author Patrick J. Gillespie, PhD

Co-Author Kayla Treat, MS, CGC

Co-Author Marco Abreu, MS

Co-Author Tae-Hwi L. Schwantes-An, PhD, MS

Co-Author Benjamin M. Helm, MS, CGC

Co-Author Fang Fang, PhD

Co-Author Xaoling Xuei, MS, PhD

Co-Author Lili R. Mantcheva, MPH, CCRP

Co-Author Kristen Suhrie, MD

Co-Author Brett H. Graham, MD, PhD

Co-Author Erin E. Conboy, MD, FACMG

Co-Author Francesco Vetrini, PhD, FACMG

Presenting Author Muqsit B. Buchh, BS

Keywords

Indiana University School of Medicine

deep intronic variant

DYNC2H1 gene

short-rib thoracic dysplasia type III

neonate

respiratory distress

Exome sequencing

RNA sequencing

quantitative droplet digital PCR

genetic diagnosis