2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Two siblings with novel compound heterozygous variants in the EXTL3 gene

Pdf Summary

This case report discusses two siblings who were found to have novel compound heterozygous variants in the EXTL3 gene. The EXTL3 gene has been associated with autosomal recessive immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA). The siblings presented with features common in ISDNA, including skeletal dysplasia, neurodevelopmental delay, and variable symptoms such as immunodeficiency, dysmorphic features, liver cysts, hypotonia, motor delay, seizures, craniosynostosis, laryngotracheal narrowing, and anal atresia. The proband's previous genetic evaluation in 2013 did not reveal any abnormalities, but in 2019, she was referred again due to osteoporosis. Physical examination showed various dysmorphic features. Exome sequencing identified two novel variants in the EXTL3 gene in the proband and her sister. Further testing showed low levels of heparan sulfate, supporting the pathogenicity of these variants. The family was provided with a diagnosis of ISDNA, which allowed them to understand the recurrence risk and consider carrier testing for the unaffected brother. The case contributes to the expansion of the phenotype associated with EXTL3 variants and highlights the variability of features observed in affected individuals. Comparative analysis with other cases in the literature revealed similarities in clinical features. References are provided for further reading on EXTL3 mutations and ISDNA.

Asset Subtitle

Co-Author - Bethanny Smith-Packard, MS, LCGC; Co-Author - Ermal Aliu, MD; Co-Author - Patricia L. Gordon, MD, FAAP, FACMG; Presenting Author - Elizaveta Makarova, BS;

Meta Tag

Cognitive Disorders

Exome sequencing

Genetic Testing

Intellectual disability

Phenotype

Phenotypic delineation of disorders

Co-Author Bethanny Smith-Packard, MS, LCGC

Co-Author Ermal Aliu, MD

Co-Author Patricia L. Gordon, MD, FAAP, FACMG

Presenting Author Elizaveta Makarova, BS

Keywords

siblings

novel variants

EXTL3 gene

ISDNA

skeletal dysplasia

neurodevelopmental delay

immunodeficiency

dysmorphic features

heparan sulfate

clinical features