Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.

Phenotypes of undiagnosed adults with actionable OTC and GLA variants.

Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: GLA, associated with Fabry disease, and OTC, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in GLA or OTC. We identified three individuals (2 male, 1 female) with PLPVs in GLA, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in OTC, two of whom were undiagnosed. All three individuals with PLPVs in GLA (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in OTC had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that GLA and OTC variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care.

Low frequency of treatable pediatric disease alleles in gnomAD: An opportunity for future genomic screening of newborns.

Hematopoietic stem cell transplant (HSCT) can prevent progression of several genetic disorders. Although a subset of these disorders are identified on newborn screening panels, others are not identified until irreversible symptoms develop. Genetic testing is an efficient methodology to ascertain pre-symptomatic children, but the penetrance of risk-associated variants in the general population is not well understood. We developed a list of 127 genes associated with disorders treatable with HSCT. We identified likely pathogenic or pathogenic (LP/P) and loss-of-function (LoF) variants in these genes in the Genome Aggregation Database (gnomAD), a dataset containing exome and genome sequencing data from 141,456 healthy adults. Within gnomAD, we identified 59 individuals with a LP/P or LoF variant in 15 genes. Genes were associated with bone marrow failure syndromes, bleeding disorders, primary immunodeficiencies, osteopetrosis, metabolic disorders, and epidermolysis bullosa. In conclusion, few ostensibly healthy adults had genotypes associated with pediatric disorders treatable with HSCTs. Given that most of these disorders do not have biomarkers that could be cheaply and universally assessed on a standard newborn screen, our data suggest that genetic testing may be a complementary approach to traditional newborn screening methodology that has the potential to improve mortality and is not expected to lead to a high burden of false-positive results.

Proposed criteria for nevoid basal cell carcinoma syndrome in children assessed using statistical optimization.

Nevoid basal cell carcinoma syndrome (NBCCS) is a tumor predisposition condition, the cardinal features of which emerge in adolescence or adulthood. Using statistical optimization, this study proposes NBCCS criteria with improved sensitivity in children less than 18 years of age. Earlier detection may lead to improved surveillance and prevention of sequelae. A survey eliciting medical history was completed by, or on behalf of, individuals with NBCCS. Based on these findings, criteria for suspicion of NBCCS in children were suggested using information from a Bernoulli naïve Bayes classifier relying on the human phenotype ontology. The sensitivity and specificity of the existing and proposed diagnostic criteria were also assessed. Participants (n = 48) reported their first signs of NBCCS appeared at a median age of 8 months, but by our retrospective analysis, they did not fulfill the current diagnostic criteria until a median age of 7 years. This study delineates the early-onset features of NBCCS and proposes criteria that should prompt consideration of NBCCS. Additionally, we demonstrate a method for quantitatively assessing the utility of diagnostic criteria for genetic disorders.

Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.

In populations that have not been selected for family history of disease, it is unclear how commonly pathogenic variants (PVs) in disease-associated genes for rare Mendelian conditions are found and how often they are associated with clinical features of these conditions. We conducted independent, prospective analyses of participants in two community-based epidemiological studies to test the hypothesis that persons carrying PVs in any of 56 genes that lead to 24 dominantly inherited, actionable conditions are more likely to exhibit the clinical features of the corresponding diseases than those without PVs. Among 462 European American Framingham Heart Study (FHS) and 3223 African-American Jackson Heart Study (JHS) participants who were exome-sequenced, we identified and classified 642 and 4429 unique variants, respectively, in these 56 genes while blinded to clinical data. In the same participants, we ascertained related clinical features from the participants' clinical history of cancer and most recent echocardiograms, electrocardiograms, and lipid measurements, without knowledge of variant classification. PVs were found in 5 FHS (1.1%) and 31 JHS (1.0%) participants. Carriers of PVs were more likely than expected, on the basis of incidence in noncarriers, to have related clinical features in both FHS (80.0% versus 12.4%) and JHS (26.9% versus 5.4%), yielding standardized incidence ratios of 6.4 [95% confidence interval (CI), 1.7 to 16.5; P = 7 × 10-4) in FHS and 4.7 (95% CI, 1.9 to 9.7; P = 3 × 10-4) in JHS. Individuals unselected for family history who carry PVs in 56 genes for actionable conditions have an increased aggregated risk of developing clinical features associated with the corresponding diseases.