2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Novel Molecular Mechanism in Malan Syndrome Uncovered through Detailed Genome Sequencing Reanalysis, Exon-level Array and RNA-seq

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Researchers have uncovered a novel molecular mechanism in Malan syndrome through detailed genome sequencing reanalysis, exon-level array, and RNA-seq. Malan syndrome is a genetic disorder caused by pathogenic variants in the NFIX gene. These variants lead to NFIX haploinsufficiency, resulting in the clinical symptoms associated with Malan syndrome. Previous studies have shown that NFIX missense variants or protein-truncating variants in exon 2 are responsible for Malan syndrome, while protein-truncating variants in exons 6-10 are associated with Marshall-Smith syndrome. <br /><br />In this case presentation, a 5-year-old male with global developmental delays and various physical anomalies was referred to the Undiagnosed Disease Network for evaluation. After extensive genetic testing that yielded no diagnosis, the patient's raw whole-genome sequencing data was reanalyzed. This led to the identification of a de novo intragenic microduplication in the NFIX gene involving exons 6 and 7. The duplication was confirmed through exon-level array analysis. Further analysis of RNA-seq data showed reduced NFIX transcript levels in fibroblasts derived from the patient. <br /><br />Based on these findings and the clinical presentation, the patient was diagnosed with Malan syndrome. The researchers recommend that when Malan or Marshall-Smith syndrome is clinically suspected but remains undiagnosed after standard genetic evaluation, the 5.9 kb recurrent copy number variation region encompassing NFIX exons 6 and 7 should be analyzed using an appropriate assay. They also highlight the importance of reanalyzing raw genomic data to identify novel molecular mechanisms and provide a definite diagnosis for patients with genetic disorders.

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Presenting Author - Jian M. Zhao, PhD; Co-Author - Nicola Longo, MD PhD FACMG; Co-Author - Robert G. Lewis, PhD; Co-Author - Thomas J. Nicholas; Co-Author - Steven E. Boyden, PhD; Co-Author - Ashley Andrews, MSN, CPNP; Co-Author - Austin Larson, MD; Co-Author - Pinar Bayrak-Toydemir; Co-Author - Lorenzo D. Botto, MD, FACMG; Co-Author - Rong Mao, MD;

Meta Tag

Bone/Joint Abnormalities

Brain/Nervous System

Etiology

Genetic Testing

Genome sequencing

Genotype-Phenotype Correlations

Intellectual disability

Malformation

Microarray

Molecular Cytogenetics

NextGen Sequencing

Phenotypic delineation of disorders

Sequencing

Variant Detection

Co-Author Nicola Longo, MD PhD FACMG

Co-Author Robert G. Lewis, PhD

Co-Author Thomas J. Nicholas

Co-Author Steven E. Boyden, PhD

Co-Author Ashley Andrews, MSN, CPNP

Co-Author Austin Larson, MD

Co-Author Pinar Bayrak-Toydemir

Co-Author Lorenzo D. Botto, MD, FACMG

Co-Author Rong Mao, MD

Presenting Author Jian M. Zhao, PhD

Keywords

Malan syndrome

molecular mechanism

genome sequencing reanalysis

exon-level array

RNA-seq

genetic disorder

NFIX gene

haploinsufficiency

Marshall-Smith syndrome

copy number variation