The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

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.

Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.