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.

Review of the genetics of thyroid tumours: diagnostic and prognostic implications.

BACKGROUND: Thyroid nodules are common, but only a small proportion harbour malignancy. Despite this, the frequency of thyroid cancer is on the increase and thyroid malignancy is the most common endocrine malignancy. Preoperative diagnosis is based on ultrasound and radionucleotide imaging as well as the fine-needle aspiration biopsy (FNAB). These biopsies yield a large proportion of indeterminate results due to inadequate material for cytological diagnosis, or due to the cytological similarity of FAs and follicular carcinomas. Recent advances in the understanding of the molecular pathogenesis of thyroid malignancy have led to the detection of characteristic genetic alterations in FNABs. This technology has the potential to increase the specificity of this test, combining cytological with genetic testing to reduce the number of indeterminate results, thereby reducing the number of thyroidectomies performed for benign disease. METHODS: This review examines the evidence for the presence of the common genetic alterations in thyroid cancer and outlines the pathological and clinical correlations of these mutations. The practicality and utility of measuring these genetic alterations in FNAB specimens is also outlined as well as the potential for these tests to alter primary management and follow-up of patients with nodular thyroid disease. CONCLUSION: It is likely that a combination of molecular testing and cytological examination of FNAB specimens will prove to be the most efficient and specific method of diagnosing thyroid cancer preoperatively.

Serum inhibin A and B concentrations during the menstrual cycle in mothers of spontaneous dizygotic twins.

Dizygotic twinning in humans is influenced by genetic factors suggesting inherited variation affects follicle development and predisposes to double ovulations. In a previous study, we conducted a detailed examination of follicle development and variation in hormone concentrations during the menstrual cycle in mothers of DZ twins (MODZT) compared with an age-matched control group of mothers of singletons. We did not detect differences in FSH concentrations between mothers of twins and mothers of singletons. Serum inhibin concentrations were measured by a radioimmunoassay that did not distinguish between dimeric inhibin A and B forms and free inhibin alpha subunit. We therefore analyzed the samples from this study with specific assays to determine whether concentrations of inhibin A and B were different between MODZT and controls and therefore contribute to the twinning phenotype. There were no significant differences between MODZT with single ovulations and control women in inhibin A and B concentrations during the cycle, including the critical period for the selection of the dominant follicle. These data suggest that the genetic cause of twinning is not associated with changes in FSH concentrations or recognised feedback mechanisms regulating FSH release.