Discovery of over 200 new and expanded genetic conditions using GeneMatcher.

GeneMatcher is a platform through which various stakeholders can connect with others interested in candidate gene findings. GeneDx, a diagnostic laboratory, has utilized GeneMatcher over the last seven years to successfully facilitate connections between clinicians and researchers, generating fruitful research collaborations. Our ultimate goal in reporting candidate gene findings is to amass sufficient evidence to establish novel disease-gene relationships (DGRs), thus providing diagnostic answers to families and clinicians. Our database of over 300,000 clinical exomes has been a major driver of DGR discovery. Our laboratory accounts for over 20% of total GeneMatcher submissions. Largely fueled by GeneMatcher matches, we have published over 200 articles involving new DGRs or expanded phenotypes for known disease-causing genes in the past three years. These endeavors require commitments to sharing data and dedicating resources to investigate potential matches. Ultimately, GeneMatcher enables collaboration on a broad scale: we are grateful to the clinicians, researchers, patients, and caregivers who have partnered with us to accelerate the pace of DGR discovery. GeneMatcher opens the door to new partnerships, new discoveries, and families finding answers that otherwise may not have been possible.

Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy.

Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance-based variant filtering. PPP1R13L encodes inhibitor of apoptosis-stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months-9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene-disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel-based genetic testing for paediatric DCM.

Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.