2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Novel Molecular Diagnoses in Individuals with Holoprosencephaly and Prior Negative Sequencing

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Holoprosencephaly (HPE) is a condition where the forebrain fails to divide properly during embryonic development, leading to brain abnormalities, facial features, and neurodevelopmental issues. HPE can occur as part of a syndrome or on its own, with genetic variations in both forms. There is a high variability of symptoms among individuals with HPE, and more severely affected individuals often inherit their genetic variant from a sub-clinically affected parent. Gene-environment interactions and oligogenic inheritance can also contribute to the variability of symptoms.<br /><br />Diagnosing HPE is challenging due to the difficulty in obtaining large cohorts and validating variants. The estimated diagnostic yield of HPE gene panels is around 25%. In this study, researchers performed whole genome sequencing on 450 individuals from 171 families who had previously received negative genetic testing for HPE. They found variants affecting known HPE genes in over a quarter of the cohort, including variants that would not have been detectable through clinical testing.<br /><br />The study highlights the value of genome sequencing in identifying novel pathogenic variants that cannot be detected through current clinical testing methods. The researchers identified aneuploidies, deep intronic splicing variants, repeat tract insertions, and structural variants that were missed by gene panels and exome sequencing. Future directions for research include examining additional genes associated with HPE, identifying novel HPE genes using different analyses, and investigating the contribution of oligogenic inheritance.<br /><br />The study also found that deletions were the most commonly called structural variants, and they identified cases of aneuploidy, including complete and partial trisomy 13. They also discovered a polyalanine expansion in the ZIC2 gene, which is known to be associated with HPE. Additionally, predicted splicing variants were found in canonical splice site positions.<br /><br />Overall, this study demonstrates the value of whole genome sequencing in improving the diagnostic yield for individuals with HPE who have received negative genetic testing. It provides insights into the genetic complexity and variability of symptoms in HPE and suggests potential avenues for further research.

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Presenting Author - Andrea Cohen, MD, PhD; Co-Author - Joel J. Hughes, DO, FACMG; Co-Author - Clifton L. Dalgard, PhD, CLS; Co-Author - Paul Kruszka, MD; Co-Author - Emmanuele Delot, PhD; Co-Author - Vincent Fusaro, PhD; Co-Author - Eric J. Vilain, MD, PhD; Co-Author - Maximilian Muenke, MD, MBA, FACMG; Co-Author - Seth I. Berger, MD, PhD;

Meta Tag

Bioinformatics

Brain/Nervous System

Congenital Anomaly

Etiology

Genetic Testing

Genome sequencing

Sequencing

Variant Detection

Co-Author Joel J. Hughes, DO, FACMG

Co-Author Clifton L. Dalgard, PhD, CLS

Co-Author Paul Kruszka, MD

Co-Author Emmanuele Delot, PhD

Co-Author Vincent Fusaro, PhD

Co-Author Eric J. Vilain, MD, PhD

Co-Author Maximilian Muenke, MD, MBA, FACMG

Co-Author Seth I. Berger, MD, PhD

Presenting Author Andrea Cohen, MD, PhD

Keywords

Holoprosencephaly

forebrain

embryonic development

brain abnormalities

facial features

genetic variations

diagnostic yield

whole genome sequencing

structural variants

genetic complexity