2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Triple molecular diagnosis of Wolf Hirschhorn syndrome, 20p duplication syndrome, and Frontotemporal dementia and/or amyotrophic lateral sclerosis.

Triple molecular diagnosis of Wolf Hirschhorn syndrome, 20p duplication syndrome, and Frontotemporal dementia and/or amyotrophic lateral sclerosis.

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This study presents a case of a 37-year-old female with Wolf Hirschhorn syndrome (WHS) who experienced dementia-like episodes. The genetic workup confirmed her WHS diagnosis and identified two additional pathogenic variants: a deletion of NSD2 in the WHS critical region and a missense variant in SQSTM1 associated with Paget disease and Frontotemporal dementia and/or amyotrophic lateral sclerosis. This suggests three molecular diagnoses: 4p16.3p16.2 loss, 20p13 gain, and the previously described SQSTM1 variant. While dual and multiple molecular diagnoses have been reported in individuals undergoing exome sequencing, no individuals with WHS have been reported to have multiple molecular diagnoses to date.<br /><br />The study aims to present a case of triple molecular genetic diagnosis involving unbalanced translocation resulting in WHS and 20p duplication along with SQSTM1-related syndrome. It also discusses the chromosomal duplications observed in individuals with WHS and the additional phenotypic features associated with these duplications.<br /><br />The patient presented with various dysmorphic features, including a short philtrum, micrognathia, high forehead, hypertelorism, exophthalmos, ptosis, high-arched and sparse eyebrows, prominent glabella, wide nasal bridge, beaked nose, short upper lip, and webbed neck. She also experienced episodes of amnesia and insomnia.<br /><br />This case highlights the potential diagnostic utility of conducting additional molecular testing in individuals with established diagnoses that may not fully explain their phenotypic presentation. It suggests that individuals with WHS may have additional molecular diagnoses that contribute to their clinical features. The study concludes by mentioning future directions for research in this field.<br /><br />Overall, this study demonstrates the importance of comprehensive genetic testing in individuals with complex clinical presentations to uncover multiple molecular diagnoses that may impact their phenotype.

Asset Subtitle

Presenting Author - Yishay Ben Moshe, MD; Co-Author - Jennifer Ellen Posey, MD, PhD;

Meta Tag

Clinical Cytogenetics

Clinical Applications of Molecular Cytogenetics

Chromosome Structure/Function

Chromosomal Abnormalities

array CGH

Sequencing

Microarray

Intellectual disability

Genetic Testing

Exome sequencing

Etiology

Delineation of Diseases

Cytogenetics

Counseling

Cognitive Disorders

Clinical History

Co-Author Jennifer Ellen Posey, MD, PhD

Presenting Author Yishay Ben Moshe, MD

Keywords

Wolf Hirschhorn syndrome

dementia-like episodes

genetic workup

NSD2 deletion

WHS critical region

SQSTM1 missense variant

Paget disease

Frontotemporal dementia

amyotrophic lateral sclerosis

molecular diagnoses