Compound genetic etiology in a patient with a syndrome including diabetes, intellectual deficiency and distichiasis.

Abstract

BACKGROUND:

We studied a young woman with atypical diabetes associated with mild intellectual disability, lymphedema distichiasis syndrome (LDS) and polymalformative syndrome including distichiasis. We used different genetic tools to identify causative pathogenic mutations and/or copy number variations.

RESULTS:

Although proband's, diabetes mellitus occurred during childhood, type 1 diabetes was unlikely due to the absence of detectable autoimmunity. DNA microarray analysis first identified a de novo, heterozygous deletion at the chr16q24.2 locus. Previously, thirty-three pathogenic or likely pathogenic deletions encompassing this locus have been reported in patients presenting with intellectual deficiency, obesity and/or lymphedema but not with diabetes. Of note, the deletion encompassed two topological association domains, whose one included FOXC2 that is known to be linked with LDS. Via whole-exome sequencing, we found a heterozygous, likely pathogenic variant in WFS1 (encoding wolframin endoplasmic reticulum [ER] transmembrane glycoprotein) which was inherited from her father who also had diabetes. WFS1 is known to be involved in monogenic diabetes. We also found a likely pathogenic variant in USP9X (encoding ubiquitin specific peptidase 9 X-linked) that is involved in X-linked intellectual disability, which was inherited from her mother who had dyscalculia and dyspraxia.

CONCLUSIONS:

Our comprehensive genetic analysis suggested that the peculiar phenotypes of our patient were possibly due to the combination of multiple genetic causes including chr16q24.2 deletion, and two likely pathogenic variants in WFS1 and USP9X.

• Authors: Lauriane Le Collen, Brigitte Delemer, Marta Spodenkiewicz, Pascale Cornillet Lefebvre, Emmanuelle Durand, Emmanuel Vaillant, Alaa Badreddine, Mehdi Derhourhi, Tarik Ait Mouhoub, Guillaume Jouret, Pauline Juttet, Pierre François Souchon, Martine Vaxillaire, Philippe Froguel, Amélie Bonnefond, Martine Doco Fenzy
• Journal: Orphanet journal of rare diseases (Orphanet J Rare Dis) Vol. 17 Issue 1 Pg. 86 (02 28 2022) ISSN: 1750-1172 [Electronic] England
• PMID: 35227307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• USP9X protein, human
• Ubiquitin Thiolesterase

Topics

• DNA Copy Number Variations (genetics)
• Diabetes Mellitus
• Eyelashes (abnormalities)
• Female
• Hair Diseases
• Heterozygote
• Humans
• Intellectual Disability (genetics)
• Lymphedema
• Phenotype
• Syndrome
• Ubiquitin Thiolesterase (genetics)