Xp11.22 duplications in four unrelated Chinese families: delineating the genotype-phenotype relationship for HSD17B10 and FGD1

Abstract

Background: Xp11.22 duplications have been reported to contribute to nonsyndromic intellectual disability (ID). The HUWE1 gene has been identified in all male Xp11.22 duplication patients and is associated with nonsyndromic ID. Currently, few Xp11.22 duplication cases have been reported in the Chinese population, with limited knowledge regarding the role of other genes in this interval. Case presentation: We investigated four unrelated Chinese male Xp11.22 duplication patients, performed a comprehensive clinical evaluation for the patients and discussed the role of other genes in this interval. All patients presented with similar clinical features, including ID, speech impairments and motor delay, which were mostly consistent with those of the Xp11.22 duplication described previously. We searched and compared all cases and noted that one of the probands (Family 1) and DECIPHER case 263,219, who carried small overlapping duplications at Xp11.22 that only covered the entire HSD17B10 gene, also suffered from ID, suggesting the important role of HSD17B10 in this interval. Furthermore, three patients (two probands in Families 3 and 4 and DECIPHER case 249, 490) had strikingly similar hypogonadism phenotypes, including micropenis, small testes and cryptorchidism, which have not been previously described in Xp11.22 duplication patients. Interestingly, the FGD1 gene was duplicated only in these three patients. Sufficient evidence has suggested that haploinsufficiency of the FGD1 gene causes Aarskog-Scott syndrome, which is characterized by hypogonadism and other abnormalities. Given that, we are the first group to propose that FGD1 may be a potential dosage-sensitive gene responsible for the hypogonadism observed in our patients. Conclusion: We reported novel genotypes and phenotypes in Chinese male Xp11.22 duplication patients, and the HSD17B10 and FGD1 genes may be involved.

Case Report: Aarskog-scott syndrome caused by FGD1 gene variation: A family study

“…The expression of the CDC42 protein was decreased in Xp11, which was predisposed to schizophrenia. A study on four unrelated Chinese male XP11.22 duplicative patients mainly with intellectual disability, language impairment, and motor delay speculated that FGD1 may have been the potential dose-sensitive gene associated with hypogonadism in these patients ( Wang et al, 2020 ). In addition, FGD1 was confirmed as a transforming growth factor-β (TGF-β), regulating guanine nucleotide conversion factor (GEF) that was involved in cytokine-induced nuclear liposome formation, which may have been part of the molecular basis of vascular lesions ( Daubon et al, 2011 ).…”

Infantile Neurodegeneration Results from Mutants of 17β-Hydroxysteroid Dehydrogenase Type 10 Rather Than Aβ-Binding Alcohol Dehydrogenase

“…This suggested that a restoration of the OMIM#300220 would be appropriate. Gene duplication of HSD17B10 also results in mental disability [58]. Since 17β-HSD10 is an essential component of mtRNase P, it was proposed [59,60] that the abnormal processing of mtRNAs is related to the pathogenesis of HSD10 mitochondrial disease.…”

FGD1 Variant Associated With Aarskog–Scott Syndrome

“…The FGD1 gene (faciogenital dysplasia 1, OMIM 300546), located at Xp11.21, encodes the RhoGEF and PH domaincontaining protein 1 (6). The FGD1 protein is made up of a proline-rich region, Dbl homology (DH), and pleckstrin homology (PH) domains, a FYVE-finger domain, and a second PH domain (PH2) from the N-terminus to the C-terminus (7).…”