Triple Genetic Diagnosis in a Patient with Late-Onset Leukodystrophy and Mild Intellectual Disability

Abstract

We describe the complex case of a 44-year-old man with polycystic kidney disease, mild cognitive impairment, and tremors in the upper limbs. Brain MRI showed lesions compatible with leukodystrophy. The diagnostic process, which included clinical exome sequencing (CES) and chromosomal microarray analysis (CMA), revealed a triple diagnosis: autosomal dominant polycystic kidney disease (ADPKD) due to a pathogenic variant, c.2152C>T-p.(Gln718Ter), in the PKD1 gene; late-onset phenylketonuria due to the presence of two missense variants, c.842C>T-p.(Pro281Leu) and c.143T>C-p.(Leu48Ser) in the PAH gene; and a 915 Kb duplication on chromosome 15. Few patients with multiple concurrent genetic diagnoses are reported in the literature; in this ADPKD patient, genome-wide analysis allowed for the diagnosis of adult-onset phenylketonuria (which would have otherwise gone unnoticed) and a 15q11.2 duplication responsible for cognitive and behavioral impairment with incomplete penetrance. This case underlines the importance of clinical genetics for interpreting complex results obtained by genome-wide techniques, and for diagnosing concurrent late-onset monogenic conditions.

Keywords: 15q11.2 duplication; CES; CMA; intellectual disability; leukodystrophy; phenylketonuria; polycystic kidney disease.

Figure 1

(a) Family tree showing autosomal dominant segregation of polycystic kidney disease: I-1, II-1, II-3, III-3 and III-5 are affected by PKD; the proband (III-5) is highlighted with a black arrow. (b) Computed tomography of the lower and upper abdomen showing enlarged kidneys with multiple hyperdense cystic formations.

Figure 2

Panels showing T2-weighted (A,C) and T1-weighted (B,D) axial brain MRI scans at the basal ganglia (A,B) and corona radiata (C,D) level. An extensive and symmetric T2 hyperintensity (A,C) black asterisks involving mainly occipital and parietal white matter was observed, with corresponding T1 slightly hypointense signal (B,D) white asterisks, sparing subcortical U-fibers and corpus callosum. T2-weighted sagittal brain MRI scans (E) showing mild vermian cerebellar atrophy (white arrow).

Figure 3

Panels showing chromosome 15q11.2 (A) and chromosome 4p16.3 (B) duplications, as reported in the UCSC Genome Browser (https://genome.ucsc.edu/, accessed on 20 November 2023) using assembly ID: GRCh37/hg19. The red frames indicate the localization of the duplicated regions on chromosome 15 and 4.