Non-syndromic intellectual disability and cataract in a patient with dual molecular diagnosis of SRD5A3 and PITX3-related diseases

<p>Objectives: Our objective was to identify the genetic cause in a patient with intellectual disability and bilateral cataracts.</p> <p>Methods: The genetic, neurological, and ophthalmological evaluations were performed. DNA samples were provided from the patient, parents, and unaffected sibs to perform whole exome sequencing (WES) and Sanger confirmation. Biochemical testing on the serum sample was performed to ascertain the clinical significance of the WES finding.</p> <p>Results: The proband presented with intellectual disability, subtle dysmorphic features, and bilateral cataracts. WES and segregation studies using Sanger sequencing revealed a homozygous missense variant of uncertain significance (VUS) in SRD5A3 and a de novo pathogenic frameshift variant in PITX3 in the proband. Biochemical analysis of serum carbohydrate-deficient-transferrin (CDT) to ascertain the significance of the VUS in SRD5A3 was consistent with a glycosylation defect and confirmed type 1, N-glycosylation defect.</p> <p>Conclusion: This case has a dual molecular diagnosis. The SRD5A3 variant with confirmed biochemical abnormality accounts for intellectual disability and subtle dysmorphic features, whereas the de novo pathogenic PITX3 variant accounts for bilateral cataracts. This case expands the severity spectrum of SRD5A3 disorder and represents a milder form. It also highlights the importance of clinical correlation and reverse phenotyping.</p>