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.

Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.

Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight.

De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females.

Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X­linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss­of­function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole­exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X­linked dominant ID, and broadens the phenotype for KIAA2022 mutations.