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.

Keywords: Childhood onset diabetes; Genetic analysis; Genetic disorders; Genotype–phenotype relations; Intellectual disability; Wolfram syndrome.

Fig. 1

Clinical features of the patient—Polymalformative syndrome including distichiasis (red arrow in a), palatine tooth (circled in red in b), uterine septum (red arrow in c), vesicoureteral reflux (d) and overweight (e). In part E we reported the increase in insulin requirement during childhood (arrow #1: 1.1 ui/kg) followed by the decrease in insulin requirement after the addition of metformin (arrow #2: 0.7 UI/kg). We show the addition effects of DPP4 inhibitors (arrow #3), and GLP1-RA (arrow #4). The dark area shows the values corresponding to overweight, while the area with points shows the values corresponding to obesity

Fig. 2

Pathogenic or likely pathogenic deletions encompassing chr16q24.2, which were found in 33 patients from Decipher and ClinGen databases

Fig. 3

Identification of two TADs (from fetal brain) encompassing the deleted region at the 16q24.2 locus. Deletion found in the patient is represented by a grey rectangle. TAD 1 and TAD 2 are represented by triangles. The deleted region, containing part of the TADs, is highlighted in red