Background:ZEB2 gene mutations or deletions cause Mowat-Wilson syndrome (MWS), which is characterized by distinctive facial features, global developmental delay, intellectual disability, epilepsy, friendly and happy personalities, congenital heart disease, Hirschsprung disease and multiple congenital anomalies. Currently, more than 300 MWS patients have been described in the literature, and nearly 280 variants in ZEB2 have been identified.Methods: In this study, we report three unrelated Chinese patients presenting multiple congenital anomalies that were consistent with those of MWS. Whole-exome sequencing (WES) was used to identify the causative variants.Results: WES identified two novel de novo frameshift variants in ZEB2 (NM_014795.4:c.2136delC, p. Lys713Serfs*3 and c.2740delG, p. Gln914Argfs*16) in patients 1 and 2, respectively, and a novel de novo splicing variant in ZEB2 (NM_014795.4:c.808-2delA) in patient 3, all of which were confirmed by Sanger sequencing. Next, we systematically reviewed the clinical characteristics of Chinese and Caucasian MWS patients. We revealed a higher incidence of constipation in Chinese MWS patients compared to that previously reported in Caucasian cohorts, while the incidence of Hirschsprung disease and happy demeanor was lower in Chinese MWS patients and that epilepsy in Chinese MWS patients could be well-controlled compared to that in Caucasian MWS individuals.Conclusion: Our study expanded the mutation spectrum of ZEB2 and enriched our understanding of the clinical characteristics of MWS. Definitive genetic diagnosis is beneficial for the genetic counseling and clinical management of individuals with MWS.
Pathogenic variants in the RASopathy-causing SHOC2 gene have been suggested to cause Noonan syndrome-like with loose anagen hair (NS/LAH). This condition is characterized by facial features resembling Noonan syndrome (NS), short stature, growth hormone deficiency (GHD), cognitive deficits, cardiac defects, and ectodermal abnormalities, including easily pluckable, sparse, thin, slow-growing hair, hyperpigmented skin and hypernasal voice. The mutation spectrum of SHOC2 is narrow, and only 8 pathogenic variants have been identified. Here, we report a 5-year-3-month-old Chinese female who displays characteristics typical of NS and has normal neurodevelopment. Trio-based whole-exome sequencing (WES) revealed a de novo variant (c.1231A>G, p.Thr411Ala) in SHOC2. This variant has been recently reported in one subject in the literature who displayed facial features typical of NS and also presented with significant speech delays, moderate intellectual disabilities, epilepsy, bilateral sensorineural deafness and renal dysplasia. The differential phenotypes between these subjects deserve to be further investigated. Next, we reviewed the clinical pictures of NS/LAH and noticed that a recurrent SHOC2 Ser2Gly variant was more likely to result in delayed neurodevelopment and short stature, compared to other SHOC2 variants. And growth hormone (GH) therapy could improve height prognosis. It was noticed that the slight sleep problems and friendly and relatively mature personality observed in our patient may be a novel phenotype of NS/LAH. Our study reconfirms the pathogenic nature of the SHOC2 Thr411Ala variant. It also provides insights into the genotype-phenotype relationship in NS/LAH and a foundation for its genetic counseling, diagnosis and treatment.
Introduction
Though an increase in Hb A2 is one of the most key markers of β‐thal carriers, a few independent cases are reported to show elevated Hb A2 levels caused by mutations in other genes beyond β‐globin gene.
Methods
We reviewed the haematological indices of 47336 individuals to analyse the phenotype–genotype correlation and identified 1439 individuals (3.04%) positive in the elevation of Hb A2. Globin and KLF1 genes analysis was performed, and further whole‐exome sequencing was carried to dissect the genetic causes of those positive samples without β‐thalassemic or KLF1 mutations.
Results
Of these 1439 individuals with elevated Hb A2, 1381 had a molecular defect in globin genes, and most were β‐thalassemic mutation; 10 had a molecular defect in KLF1 gene. Finally, among the 38 individuals without β‐thalassemic or KLF1 mutations, 7 were identified to carried a loss‐of‐function mutation in SUPT5H.
Conclusion
This study has provided a mutation spectrum of SUPT5H in a cohort screening leading to the elevation of Hb A2. According to the previous observations that individuals with a combination of β‐thal mutation and a SUPT5H variant might present moderate β‐thaelassemia, these findings emphasized the importance of comprehensive molecular diagnosis to prevent birth defects of β‐thaelassemia caused by rare mutations from modifier genes.
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