2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Continuing the continuum: Molecular and phenotypic spectrum of <em>ACSL4</em> intellectual developmental disorder

Pdf Summary

This study aimed to expand the understanding of ACSL4-related intellectual developmental disorder (IDD) by analyzing the molecular and phenotypic spectrum of the disease. ACSL4 is a gene involved in lipid metabolism and has been associated with IDD in a limited number of patients. The researchers surveyed the literature, public genomic resources, and clinical databases to gather data on ACSL4-related disease. They then used computational approaches to analyze the findings and determine genotype-phenotype correlations.<br /><br />The study identified six novel variants in the ACSL4 gene in eight individuals, including the first disease-associated in-frame deletion. Phenotypic profiling revealed that IDD and speech delays were the main features of the disease, with variable occurrences of microcephaly. Computational analysis highlighted functionally important residues of the ACSL4 protein, including variants of uncertain significance (VUSs) that may have protein altering properties.<br /><br />The prevalence of different phenotypic features in the newly identified patients was compared to that in previously identified patients with ACSL4 disease-associated variants. The study found that IDD and speech delays were consistently observed in both groups, indicating their significance in ACSL4-related IDD.<br /><br />The molecular findings were annotated using NM_004458.3, and pathogenic, likely pathogenic, and variants of uncertain significance were assessed using combined annotation dependent depletion (CADD) and DDgun scores. The results were compared to determine the potential pathogenicity of each variant.<br /><br />Overall, this study expanded the phenotypic spectrum of ACSL4-related IDD and provided insights into the molecular characteristics of the disease. The identification of novel variants and their association with specific phenotypic features contributes to a better understanding of the disorder and may aid in diagnosis and treatment approaches.

Asset Subtitle

Presenting Author - Clayton Del Pico, BS; Co-Author - Lisa A. Lansdon, PhD; Submitter Only - Matthew Speranza, BS; Submitter Only - Janda Jenkins, MS, CGC; Submitter Only - Dihong Zhou, MD; Submitter Only - Florence Jobic, DES; Submitter Only - Perrine Brunelle, DES; Submitter Only - Penelope E. Bonnen, PhD; Submitter Only - Michael J. Schnieders, DSc; Submitter Only - Joseph T. Alaimo, PhD, FACMG;

Meta Tag

Genotype-Phenotype Correlations

Intellectual disability

Phenotypic delineation of disorders

X-Inactivation/X-Linked Disease

Co-Author Lisa A. Lansdon, PhD

Presenting Author Clayton Del Pico, BS

Submitter Only Matthew Speranza, BS

Submitter Only Janda Jenkins, MS, CGC

Submitter Only Dihong Zhou, MD

Submitter Only Florence Jobic, DES

Submitter Only Perrine Brunelle, DES

Submitter Only Penelope E. Bonnen, PhD

Submitter Only Michael J. Schnieders, DSc

Submitter Only Joseph T. Alaimo, PhD, FACMG

Keywords

ACSL4-related IDD

gene

lipid metabolism

phenotypic spectrum

variants

in-frame deletion

microcephaly

speech delays

computational analysis

diagnosis