Phenome-wide profiling identifies genotype-phenotype associations in Phelan-McDermid syndrome using family-sourced data from an international registry

Abstract

Background: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by 22q13 deletions that include the SHANK3 gene or pathogenic sequence variants in SHANK3. It is characterized by global developmental delay, intellectual disability, speech impairment, autism spectrum disorder, and hypotonia; other variable features include epilepsy, brain and renal malformations, and mild dysmorphic features. Here, we conducted genotype-phenotype correlation analyses using the PMS International Registry, a family-driven registry that compiles clinical data in the form of family-reported outcomes and family-sourced genetic test results.

Methods: Data from the registry were harmonized and integrated into the i2b2/tranSMART clinical and genomics data warehouse. We gathered information from 401 individuals with 22q13 deletions including SHANK3 (n = 350, ranging in size from 10 kb to 9.1 Mb) or pathogenic or likely pathogenic SHANK3 sequence variants (n = 51), and used regression models with deletion size as a potential predictor of clinical outcomes for 328 phenotypes.

Results: Our results showed that increased deletion size was significantly associated with delay in gross and fine motor acquisitions, a spectrum of conditions related to poor muscle tone, renal malformations, mild dysmorphic features (e.g., large fleshy hands, sacral dimple, dysplastic toenails, supernumerary teeth), lymphedema, congenital heart defects, and more frequent neuroimaging abnormalities and infections. These findings indicate that genes upstream of SHANK3 also contribute to some of the manifestations of PMS in individuals with larger deletions. We also showed that self-help skills, verbal ability and a range of psychiatric diagnoses (e.g., autism, ADHD, anxiety disorder) were more common among individuals with smaller deletions and SHANK3 variants.

Limitations: Some participants were tested with targeted 22q microarrays rather than genome-wide arrays, and karyotypes were unavailable in many cases, thus precluding the analysis of the effect of other copy number variants or chromosomal rearrangements on the phenotype.

Conclusions: This is the largest reported case series of individuals with PMS. Overall, we demonstrate the feasibility of using data from a family-sourced registry to conduct genotype-phenotype analyses in rare genetic disorders. We replicate and strengthen previous findings, and reveal novel associations between larger 22q13 deletions and congenital heart defects, neuroimaging abnormalities and recurrent infections.

Keywords: SHANK3; 22q13.3 deletion; Phelan-McDermid syndrome; Phenome-wide association study.

Fig. 1

Genetic variants affecting SHANK3 in 401 PMS patients included in the study. Each line represents a patient; deletions are shown in red and SHANK3 sequence variants in blue. For simplicity, sequence variants are represented as overlapping the whole gene. SHANK3 is indicated by an arrow. Chromosomal coordinates are based on the GRCh38 genome build. Constrained genes intolerant to loss-of-function variants as measured by the LOEUF (loss-of-function observed/expected upper bound fraction) metric from gnomAD (v2.1.1) are indicated in orange (LOEUF < 0.2 darker orange, < 0.3 lighter orange; smaller LOEUF indicates higher constraint)

Fig. 2

Association between deletion size and age of acquisition of gross motor milestones. On the left: deletions (in red) and SHANK3 variants (asterisks), ordered by decreasing deletion size/position. The position of SHANK3 is indicated by a vertical line. On the right: status of each patient for developmental gross motor phenotypes, lined up with the respective genetic status. The shades of gray and black represent the age range at which the patients achieved gross motor milestones, with lighter shades indicating younger ages and darker shades indicating older ages. The color white indicates that the answer was either 'not applicable' or 'unsure'

Fig. 3

Association between deletion size and renal abnormalities. On the left: deletions (in red) and SHANK3 variants (asterisks), ordered by decreasing deletion size/position. The positions of SHANK3 and CELSR1, recently implicated in renal defects, are indicated by vertical lines. On the right: status of each patient for renal conditions, lined up with the respective genetic status. The color black indicates the presence of the phenotype, gray indicates the absence of the phenotype, and white indicates missing information

Fig. 4

Association between deletion size and lymphatic-related conditions. On the left: deletions (in red) and SHANK3 variants (asterisks), ordered by decreasing deletion size/position. The positions of SHANK3 and CELSR1, recently implicated in lymphedema, are indicated by vertical lines. On the right: status of each patient for lymphatic-related conditions, lined up with the respective genetic status. The color black indicates the presence of the phenotype, gray indicates the absence of the phenotype, and white indicates missing information