Duplication at 19q13.32q13.33 Segregating with Neuropsychiatric Phenotype in a Three-Generation Family: Towards the Definition of a Critical Region

Abstract

Chromosomal submicroscopic imbalances represent well-known causes of neurodevelopmental disorders. In some cases, these can cause specific autosomal dominant syndromes, with high-to-complete penetrance and de novo occurrence of the variant. In other cases, they result in non-syndromic neurodevelopmental disorders, often acting as moderate-penetrance risk factors, possibly inherited from unaffected parents. We describe a three-generation family with non-syndromic neuropsychiatric features segregating with a novel 19q13.32q13.33 microduplication. The propositus was a 28-month-old male ascertained for psychomotor delay, with no dysmorphic features or malformations. His mother had Attention-Deficit/Hyperactivity Disorder and a learning disability. The maternal uncle had an intellectual disability. Chromosomal microarray analysis identified a 969 kb 19q13.32q13.33 microduplication in the proband. The variant segregated in the mother, the uncle, and the maternal grandmother of the proband, who also presented neuropsychiatric disorders. Fragile-X Syndrome testing was negative. Exome Sequencing did not identify Pathogenic/Likely Pathogenic variants. Imbalances involving 19q13.32 and 19q13.33 are associated with neurodevelopmental delay. A review of the reported microduplications allowed to propose BICRA (MIM *605690) and KPTN (MIM *615620) as candidates for the neurodevelopmental delay susceptibility in 19q13.32q13.33 copy number gains. The peculiarities of this case are the small extension of the duplication, the three-generation segregation, and the full penetrance of the phenotype.

Keywords: 19q13.32q13.33 microduplication; BICRA; KPTN; chromosomal microarray analysis; copy number gain; neurodevelopmental delay.

Figure 1

Pedigree of the family. Roman numbers (I, II, III) define generations within the family. Arabic numbers (1, 2, 3, 4) define individuals within each generation.

Figure 2

(A) The extra copy of the 19q13.32q13.33 region identified by SNP-array in the present case, detailed in (C), compared with the other overlapping gains (<3 Mb in size) reported on the DECIPHER database (https://www.deciphergenomics.org/; hg38 release. Last accessed 30 August 2023). Vertical lines highlight the potential candidate genes (KPTN, BICRA, and ZSWIM9) and dotted lines and orange area indicate a fourth candidate area shared by several cases and including a regulatory region of the BICRA gene, as reported on the UCSC browser (https://genome.ucsc.edu/ (Last accessed on 30 August 2023); hg38 release) (B). The source files for the image are provided in Supplementary Materials Figure S1.