genetic etiology
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Author(s):  
Jie-Yuan Jin ◽  
Pan-Feng Wu ◽  
Fang-Mei Luo ◽  
Bing-Bing Guo ◽  
Lei Zeng ◽  
...  

Background: Preaxial polydactyly (PPD) is one of the most common developmental malformations, with a prevalence of 0.8–1.4% in Asians. PPD is divided into four types, PPD I–IV, and PPD I is the most frequent type. Only six loci (GLI1, GLI3, STKLD1, ZRS, pre-ZRS, and a deletion located 240 kb from SHH) have been identified in non-syndromic PPD cases. However, pathogenesis of most PPD patients has never been investigated. This study aimed to understand the genetic mechanisms involved in the etiology of PPD I in a family with multiple affected members.Methods: We recruited a PPD I family (PPD001) and used stepwise genetic analysis to determine the genetic etiology. In addition, for functional validation of the identified GLIS1 variant, in vitro studies were conducted. GLIS1 variants were further screened in additional 155 PPD cases.Results: We identified a GLIS1 variant (NM_147193: c.1061G > A, p.R354H) in the PPD001 family. In vitro studies showed that this variant decreased the nuclear translocation of GLIS1 and resulted in increased cell viability and migration. RNA sequencing revealed abnormal TBX4 and SFRP2 expression in 293T cells transfected with mutant GLIS1. Additionally, we identified a GLIS1 variant (c.664G > A, p.D222N) in another PPD case.Conclusion: We identified two GLIS1 variants in PPD I patients and first linked GLIS1 with PPD I. Our findings contributed to future molecular and clinical diagnosis of PPD and deepened our knowledge of this disease.


2022 ◽  
Vol 0 (0) ◽  
pp. 0
Author(s):  
Zirui Dong ◽  
MatthewHoi Kin Chau ◽  
Ying Li ◽  
Peng Dai ◽  
Mengmeng Shi ◽  
...  

Endocrines ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 1-15
Author(s):  
Ali Kemal Topaloglu ◽  
Ihsan Turan

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.


2021 ◽  
Author(s):  
Meiying Cai ◽  
Xiangqun Fan ◽  
Xuemei Chen ◽  
Shiyi Xu ◽  
Xiangguo Fu ◽  
...  

Abstract Aberrant right subclavian artery (ARSA) is becoming more common in fetuses. However, there are relatively few studies on the genetic etiology of ARSA. We performed genetic analysis on fetuses with ARSA and followed up the pregnancy outcome to evaluate the prognosis of the fetuses, providing information for prenatal and eugenics consultations. A retrospective study was conducted on 112 pregnant women with fetuses diagnosed with ARSA from December 2016 to February 2021. Karyotype analysis and single-nucleotide polymorphism array (SNP-array) were performed in 112 fetuses. The 112 fetuses were divided into two groups: ARSA group, 48 (42.9%) and ARSA with other ultrasound abnormalities group, 64 (57.1%) cases. The total rate of pathogenic copy number variation (CNV) was 7.1% (8/112) using karyotype analysis (3/8) and SNP-array (5/8). The rate of pathogenic CNV in isolated ARSA and ARSA combined with other ultrasound abnormalities were 4.2% (2/48) and 9.4% (6/64), respectively. There was no significant difference between the two groups (P=0.463). The results of genetic analysis influence parents' decision to terminate the pregnancy. During follow-up, fetuses with ARSA without pathogenic CNV were found to have normal growth and development after birth. Therefore, prenatal genetic counseling and SNP-array should be recommended to better assess fetal prognosis.


Neonatology ◽  
2021 ◽  
pp. 1-8
Author(s):  
Liyuan Hu ◽  
Lin Yang ◽  
Kai Yan ◽  
Bingbing Wu ◽  
Huijun Wang ◽  
...  

<b><i>Objectives:</i></b> The genetic characteristics in neonates admitted to the NICU with recurrent hypernatremia remained unknown. We aimed to implement early genetic sequencing to identify possible genetic etiologies, optimize the treatment, and improve the outcome. <b><i>Methods:</i></b> We prospectively performed exome sequencing or targeted panel sequencing on neonates diagnosed with recurrent hypernatremia (plasma sodium ≥150 mEq/L, ≥2 episodes) from January 1, 2016, to June 30, 2020. <b><i>Results:</i></b> Among 22,375 neonates admitted to the NICU, approximately 0.33% (73/22,375) developed hypernatremia. The incidence of hypernatremia &#x3e;14 days and ≤14 days was 0.03% and 0.3%, respectively. Among 38 neonates who had ≥2 hypernatremia episodes, parents of 28 patients consented for sequencing. Genetic diagnosis was achieved in 25% neonates (7/28). Precision medicine treatment was performed in 85.7% (6/7) of the patients, including hydrochlorothiazide and indomethacin for 57.1% (4/7) with arginine vasopressin receptor 2 (<i>AVPR2</i>) deficiency-associated congenital nephrogenic diabetes insipidus; a special diet of fructose formula for 1 patient with solute carrier family 5 member 1 deficiency-associated congenital glucose-galactose malabsorption (1/7, 14.3%); and kallikrein-inhibiting ointment for 1 patient with serine protease inhibitor of Kazal-type <i>5</i> deficiency-associated Netherton syndrome (1/7, 14.3%). Only hypernatremia onset age (adjusted odds ratio 1.32 [1.01–1.72], <i>p</i> = 0.040) independently predicted the underlying genetic etiology. The risk of a genetic etiology of hypernatremia was 9.0 times higher for neonates with a hypernatremia onset age ≥17.5 days (95% confidence interval, 1.1–73.2; <i>p</i> = 0.038). <b><i>Conclusions:</i></b> Single-gene disorders are common in neonates with recurrent hypernatremia, and &#x3e;50% of cases are caused by <i>AVPR2</i> deficiency-associated congenital nephrogenic diabetes insipidus. Early genetic testing can aid the diagnosis of unexplained recurrent neonatal hypernatremia and improve therapy and outcome.


2021 ◽  
Vol 4 (6) ◽  
pp. 25673-25677
Author(s):  
Daniel Alencar De Araújo ◽  
Denise Teixeira Santos ◽  
Larisse Yara De Carvalho ◽  
Daniela Moura Parente

2021 ◽  
Author(s):  
Guillaume Martinez ◽  
Charles Coutton ◽  
Corinne Loeuillet ◽  
Caroline Cazin ◽  
Jana Muroňová ◽  
...  

Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects – the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man.


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