2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Genome Sequence Re-Analysis Reveals De-Novo FBXW7 Canonical Splice Variant in Newly Described Neurodevelopmental Syndrome

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This research poster presentation discusses the case of a 16-month-old male with global developmental delay and various other phenotypic features. The patient presented with macrocephaly, obesity, overgrowth, hypotonia, distinctive facial features, and a history of hypocalcemia and hyperphosphatemia. The patient's brother also had autistic features but no other remarkable family history was reported. The initial genetic testing, including Fragile X and microarray, was negative. However, a clinician-initiated re-analysis of the whole genome sequencing (WGS) data identified a de novo variant in the FBXW7 gene, specifically in the canonical splice donor site of intron 11.<br /><br />FBXW7 is a tumor suppressor gene located on chromosome 4q31.3. While it is commonly associated with somatic human cancer cells, recent studies have shown that germline pathogenic variants in FBXW7 can cause a syndromic neurodevelopmental disorder. The variant identified in this case was absent from population databases and the patient's brother, and in-silico tools predicted that it interferes with splicing and results in the loss of normal protein function.<br /><br />The case highlights the importance of reanalyzing WGS data in the presence of new literature and disease database updates. It also emphasizes the potential of WGS in identifying new gene-disease associations across multiple variant types. The authors note that obesity and overgrowth are potentially new associations expanding the phenotypic spectrum of FBXW7-related neurodevelopmental disorder.<br /><br />However, it should be noted that cancer has not been reported in individuals with FBXW7-related neurodevelopmental syndrome, suggesting that additional studies and monitoring may be necessary. The study concludes that the re-analysis of WGS data can provide valuable insights into genetic etiologies in patients with developmental delay and other phenotypic features.<br /><br />The research was conducted at the Rady Children's Institute for Genomic Medicine using WGS data analyzed with the Illumina DRAGEN software. The variant prioritization and clinical reporting were performed using Fabric Enterprise.

Asset Subtitle

Presenting Author - Daniel C. Helbling, MS; Co-Author - Jerica L. Lenberg, MS, LCGC; Co-Author - Arivudainambi Ramalingam, PhD, FACMG; Co-Author - Kristen Wigby, MD;

Meta Tag

Clinical History

Cognitive Disorders

Dysmorphology

Genetic Testing

Genome sequencing

Identification of Disease Genes

NextGen Sequencing

Phenotype

Sequencing

Variant Detection

Co-Author Jerica L. Lenberg, MS, LCGC

Co-Author Arivudainambi Ramalingam, PhD, FACMG

Co-Author Kristen Wigby, MD

Presenting Author Daniel C. Helbling, MS

Keywords

16-month-old male

global developmental delay

phenotypic features

macrocephaly

obesity

hypotonia

FBXW7 gene

syndromic neurodevelopmental disorder

WGS data

genetic etiologies