Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11-q13 imprinting region

Abstract

Background: The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11-q13 duplication syndrome (resulting from the two common forms of duplications-either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region.

Methods: Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11-q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms.

Results: This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11-q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11-q13 duplication syndrome.

Conclusion: Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype-phenotype correlation for patients impacted by variable structural variations within the 15q11-q13 region.

Keywords: 15q11–q13 duplication syndrome (Dup15q syndrome); Angelman syndrome; Prader–Willi syndrome; chromosome 15q11–q13 region.

FIGURE 1

Comprehensive genetic and clinical analysis of eight patients. (a) Illustration of the detected copy number variations (CNVs) in eight patients using chromosomal microarray. Above, the genes and previously reported breakpoints in the 15q11–q13 region are shown in their relative genomic positions. Below are shown BP1–BP3 and the observed deletions and duplications in all the patients. The blue and red bars represent the gross duplications and deletions associated with Prader–Willi syndrome (PWS)/Angelman syndrome (AS)/15q_duplication syndrome, whereas the brown bars indicate the breakpoints. The UCSC genome browser was used to map the estimated base positions for the deleted or duplicated regions to human genome assembly hg38. Type 1 deletion between BP1–BP3 (GRCh38 chr15:23123714‐28193120) and type 2 deletion between BP2 and BP3 (GRCh38 chr15:23374765‐28193120). BP1–BP3 are breakpoints 1–3, respectively. (b) Copy number estimation using digital droplet PCR (ddPCR). The y‐axis represents the absolute copy number estimation for each of the patient samples. Each patient experiment has three replicates that show consistent CNV counts. (c) Bar plot showing detected CNVs by ddPCR. The red and blue bars represent the deletions and duplications, respectively.

FIGURE 2

Deep clinical phenotypic profiling, including diagnosed disease, for all eight patients.