2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Novel Variants in <em>EFL1</em> Lead to a Potential Diagnosis of Shwachman-Diamond Syndrome 2

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A ten-year-old girl presented with a bone disorder characterized by short stature, metaphyseal irregularities, abnormal shape of vertebrae, and widened ribs, consistent with a form of spondylometaphyseal dysplasia. Previous genetic testing did not yield any significant findings. However, reanalysis of whole genome sequencing data identified compound heterozygous variants in the EFL1 gene, which has been associated with Shwachman-Diamond syndrome 2 (SDS2). SDS2 is characterized by exocrine pancreatic dysfunction, hematopoietic abnormalities, short stature, and metaphyseal dysplasia. The patient’s phenotype matched many of the symptoms of SDS2, but with less pronounced pancreatic insufficiency and hematopoietic symptoms. Fecal elastase levels were normal, but blood lipase levels were slightly high and blood amylase levels were slightly low, indicating mild pancreatic dysfunction. Bone marrow analysis revealed hypocellular marrow with normal maturation and no dysplasia. The patient’s attenuated phenotype may be due to a partial splicing defect in both copies of EFL1. RNA sequencing is planned for further confirmation and detail of the splicing defects. The patient is currently being followed clinically according to SDS1 guidelines. Compound heterozygous inherited variants in the EFL1 gene were detected, with one variant disrupting the splice donor site of intron 9 and the other creating a novel splice acceptor site in intron 4, resulting in an out-of-frame transcript.

Asset Subtitle

Presenting Author - John M. O'Shea, PhD; Co-Author - Jian M. Zhao, PhD; Co-Author - Pinar Bayrak-Toydemir; Co-Author - David H. Viskochil, MD, PhD; Co-Author - Ashley Andrews, MSN, CPNP; Co-Author - Lorenzo D. Botto, MD, FACMG; Co-Author - Rong Mao, MD;

Meta Tag

Bone/Joint Abnormalities

Genome sequencing

NextGen Sequencing

Sequencing

Co-Author Jian M. Zhao, PhD

Co-Author Pinar Bayrak-Toydemir

Co-Author David H. Viskochil, MD, PhD

Co-Author Ashley Andrews, MSN, CPNP

Co-Author Lorenzo D. Botto, MD, FACMG

Co-Author Rong Mao, MD

Presenting Author John M. O'Shea, PhD

Keywords

bone disorder

short stature

metaphyseal irregularities

EFL1 gene

Shwachman-Diamond syndrome 2

exocrine pancreatic dysfunction

hematopoietic abnormalities

pancreatic insufficiency

splicing defects

attenuated phenotype