A Novel Frameshift CHD4 Variant Leading to Sifrim-Hitz-Weiss Syndrome in a Proband with a Subclinical Familial t(17;19) and a Large dup(2)(q14.3q21.1)

• Published in: Biomedicines Vol. 11; no. 1; p. 12
• Main Authors: Da Silva, Jorge Diogo, Oliva-Teles, Natália, Tkachenko, Nataliya, Fino, Joana, Marques, Mariana, Fortuna, Ana Maria, David, Dezso
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.01.2023; MDPI
• Subjects: Aggressiveness; Alzheimer's disease; Behavior disorders; Case Report; CHD4-associated ND phenotype; Chromosomes; DNA helicase; dup(q14.3q21.1); familial translocation; frameshift CHD4 variant; Genetic diversity; Genomes; Genomics; Genotype & phenotype; GSG1L2; Intellectual disabilities; Neurodevelopmental disorders; Patients; Phenotypes; Phenotyping; Sifrim–Hitz–Weiss syndrome; Young adults; United States > US; familial translocation; dup(q14.3q21.1); frameshift CHD4 variant; Sifrim–Hitz–Weiss syndrome; CHD4-associated ND phenotype; GSG1L2
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11010012

The genetic complexity of neurodevelopmental disorders (NDD), combined with a heterogeneous clinical presentation, makes accurate assessment of their molecular bases and pathogenic mechanisms challenging. Our purpose is to reveal the pathogenic variant underlying a complex NDD through identification of the "full" spectrum of structural genomic and genetic variants. Therefore, clinical phenotyping and identification of variants by genome and exome sequencing, together with comprehensive assessment of these and affected candidate genes, were carried out. A maternally-inherited familial translocation [t(17;19)(p13.1;p13.3)mat] disrupting the GSG1 like 2 gene ( ), a 3.2 Mb dup(2)(q14.3q21.1) encompassing the autosomal dominant OMIM phenotype-associated and gene, and a novel frameshift c.4442del, p.(Gly1481Valfs*21) variant within exon 30 of the Chromodomain helicase DNA binding protein 4 ( ) have been identified. Considering the pathogenic potential of each variant and the proband's phenotype, we conclude that this case basically fits the Sifrim-Hitz-Weiss syndrome or -associated neurodevelopmental phenotype. Finally, our data highlight the need for identification of the "full" spectrum of structural genomic and genetic variants and of reverse comparative phenotyping, including unrelated patients with variants in same genes, for improved genomic healthcare of patients with NDD.