scholarly journals Genotypic and phenotypic spectrum of CCDC141 variants in a Chinese cohort with congenital hypogonadotropic hypogonadism

2020 ◽  
Vol 183 (3) ◽  
pp. 245-254
Author(s):  
Qiao Hou ◽  
Jiayu Wu ◽  
Yaguang Zhao ◽  
Xinying Wang ◽  
Fang Jiang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Segregation Analysis ◽  
Hypogonadotropic Hypogonadism ◽  
Sex Steroid ◽  
Phenotypic Spectrum ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Whole Exome ◽  
Chinese Cohort

Objective: To identify CCDC141 variants in a large Chinese cohort with congenital hypogonadotropic hypogonadism (CHH) and to assess the contribution of CCDC141 to CHH. Design: Detailed phenotyping was conducted in CHH patients with CCDC141 variants and co-segregation analysis was performed, when possible. Methods: Whole-exome sequencing was performed in 177 CHH patients and 450 unrelated, ethnically matched controls from China. Results: Seven novel CCDC141 rare sequencing variants (RSVs) were identified in 12 CHH pedigrees. Four of the variants were private mutations; however, p.Q409X, p.Q871X and p.G1488S were identified in more than one patient. Up to 75% (9/12) of patients had mutations in other CHH-associated genes, which is significantly higher than CHH patients without CCDC141 RSVs. The co-segregation analysis for eight CHH families showed that 75% (6/8) CCDC141 RSVs were inherited from their fertile parents. Over half (58.3%, 8/18) of the patients exhibited other clinical deformities in addition to hypogonadism. One patient harbouring a CCDC141 RSV showed a reversal of CHH after sex-steroid replacement. Conclusions: Our results broaden the genotypic spectrum of CCDC141 in CHH, as CCDC141 RSVs alone do not appear sufficient to cause CHH. The phenotypic spectrum in patients with CCDC141 RSVs is much wider than originally believed.

Whole exome sequencing in congenital hypogonadotropic hypogonadism

2015 ◽  
Author(s):  
Louise Izatt ◽  
Paul Carroll ◽  
Suzanne Lillis ◽  
Lina Brodd ◽  
Kristina Stone ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hypogonadotropic Hypogonadism ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Whole Exome

Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism

2020 ◽  
Vol 58 (1) ◽  
pp. 66-72
Author(s):  
Meichao Men ◽  
Xinying Wang ◽  
Jiayu Wu ◽  
Wang Zeng ◽  
Fang Jiang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Sanger Sequencing ◽  
Segregation Analysis ◽  
Autosomal Dominant ◽  
Hypogonadotropic Hypogonadism ◽  
Chinese Patients ◽  
Biological Processes ◽  
Blue Colour ◽  
Whole Exome ◽  
Chinese Cohort

BackgroundFGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including DUSP6, IL17RD, SPRY2 and SPRY4. The aim of this study was to investigate the genotypic and phenotypic spectra of these genes in a large cohort of Chinese patients with IHH.MethodsA total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing.ResultsFour heterozygous DUSP6 variants (p.S157I, p.R83Q, p.P188L and p.N355I) were found in six patients. Cryptorchidism, dental agenesis, syndactyly and blue colour blindness were commonly observed in patients with DUSP6 mutations. Six heterozygous IL17RD variants (p.P191L, p.G35V, p.S671L, p.A221T, p.I329M and p.I329V) were found in seven patients. Segregation analysis indicated that 100% (5/5) of probands inherited the IL17RD variants from their unaffected parents, and oligogenicity was found in 4/7 patients. One rare SPRY4 variant (p.T68S) was found in a female patient with Kallmann syndrome who also carried a PLXNA1 mutation.ConclusionOur study greatly enriched the genotypic and phenotypic spectra of DUSP6, IL17RD and SPRY4 in IHH. Mutations in DUSP6 alone seem sufficient to cause IHH in an autosomal dominant manner, whereas IL17RD or SPRY4 mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes.

Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: a retrospective study

2014 ◽  
Vol 88 (1) ◽  
pp. 34-40 ◽  
Author(s):  
D.A. Dyment ◽  
M. Tétreault ◽  
C.L. Beaulieu ◽  
T. Hartley ◽  
P. Ferreira ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Pediatric Epilepsy ◽  
Phenotypic Spectrum ◽  
Whole Exome

scholarly journals Case Report: Identification of a de novo Microdeletion 1q44 in a Patient With Seizures and Developmental Delay

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiehen Tung ◽  
Haiying Lu ◽  
Wenxin Lin ◽  
Tingting Huang ◽  
Samuel Kim ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Clinical Symptoms ◽  
Karyotype Analysis ◽  
Microdeletion Syndrome ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
Number Variation ◽  
History Of

Objective: 1q44 microdeletion syndrome is difficult to diagnose due to the wide phenotypic spectrum and strong genetic heterogeneity. We explore the correlation between the chromosome microdeletions and phenotype in a child with 1q44 microdeletion syndrome, we collected the clinical features of the patient and combined them with adjacent copy number variation (CNV) regions previously reported.Methods: We collected the full medical history of the patient and summarized her clinical symptoms. Whole-exome sequencing (WES) and CapCNV analysis were performed with DNA extracted from both the patient's and her parents' peripheral blood samples. Fluorescent quantitative PCR (q-PCR) was performed for the use of verification to the CNV regions.Results: A 28.7 KB microdeletion was detected in the 1q44 region by whole-exome sequencing and low-depth whole-genome sequencing. The deleted region included the genes COX20 and HNRNPU. As verification, karyotype analysis showed no abnormality, and the results of qPCR were consistent with that of whole-exome sequencing and CapCNV analysis.Conclusion: The patient was diagnosed with 1q44 microdeletion syndrome with clinical and genetic analysis. Analyzing both whole-exome sequencing and CapCNV analysis can not only improve the diagnostic rate of clinically suspected syndromes that present with intellectual disability (ID) and multiple malformations but also support further study of the correlation between CNVs and clinical phenotypes. This study lays the foundation for the further study of the pathogenesis of complex diseases.

Homozygous TANGO2 Single Nucleotide Variants Presenting with Additional Manifestations Resembling Alternating Hemiplegia of Childhood–Expanding the Phenotype of a Recently Reported Condition

2019 ◽  
Vol 50 (02) ◽  
pp. 122-125 ◽  
Author(s):  
Melissa Hicks ◽  
A.H.M. Huq ◽  
Rajkumar Agarwal ◽  
Kuntal Sen
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cardiac Arrhythmias ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Alternating Hemiplegia Of Childhood ◽  
Phenotypic Spectrum ◽  
Indian Girl ◽  
Whole Exome ◽  
Work Up

Case We report a 15-year-old Indian girl born to a consanguineous couple, who presented with epilepsy, developmental delay, neuroregression, and episodes of alternating hemiparesis. In addition, she had one episode of rhabdomyolysis at the age of 7 years. Extensive genetic and metabolic work up through the years was unrevealing. Eventually a trio whole exome sequencing (WES) revealed homozygous single nucleotide variants in TANGO2 gene. Discussion TANGO2 related recurrent metabolic crises with encephalomyopathy and cardiac arrhythmias were described very recently and only 15 cases were reported in literature at the time of writing. Alternating hemiplegia of childhood which was seen in our patient, has not been described in previous patients with TANGO2 mutation, and thereby expands the emerging phenotypic spectrum of this novel entity. This report also reiterates the utility of WES in diagnosing newly recognized neurogenetic conditions.

scholarly journals New insights from unbiased panel and whole-exome sequencing in a large Chinese cohort with disorders of sex development

2019 ◽  
Vol 181 (3) ◽  
pp. 311-323 ◽  
Author(s):  
Yufei Xu ◽  
Yirou Wang ◽  
Niu Li ◽  
Ruen Yao ◽  
Guoqiang Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Large Scale ◽  
Copy Number Variants ◽  
Disorders Of Sex Development ◽  
Variant Of Uncertain Significance ◽  
Sex Development ◽  
Whole Exome ◽  
Chinese Cohort ◽  
Panel Sequencing

Context Diagnosis of non-chromosomal type disorders of sex development (DSD) has long been challenging. There is still no research on overview of a large Chinese DSD cohort. Objective To determine the etiologic diagnosis through unbiased large-scale panel sequencing and whole-exome sequencing (WES) within a large Chinese DSD cohort. Design Patients were recruited according to the inclusion criteria of DSD. The applied panel contains 2742 known disease-causing genes, including all known diagnostic genes for DSD. Methods Targeted panel sequencing (TPS) was performed, and identified candidate variants were verified. Variant pathogenicities were evaluated according to established guidelines. WES was performed for randomly selected negative samples. Results This study included 125 patients. Seventy-five variants were identified by TPS and 31 variants were reported for the first time. Pathogenic and likely pathogenic variants accounted for 38.7 and 30.7%, respectively. On the basis of clinical certainty, etiologic diagnostic rates of 46.9 and 10.3% were obtained for 46,XY and 46,XX DSD patients, respectively. We reported novel candidate genes (BMPR1B, GNAS, GHR) and regions of copy number variants outside the expected DSD genotype–phenotype correlation and determined a founder mutation (SRD5A2 p.R227Q) in patients with 5α-reductase deficiency. Further WES in randomly selected negative samples identified only one among 14 negative samples as a variant of uncertain significance, indicating that WES did not improve the diagnostic rate. Conclusions This is the first report of the applying unbiased TPS in a large Chinese cohort of patients with 46,XY and 46,XX DSD. Our findings expand the gene, mutation and phenotype spectra of the rare types of DSD in the Chinese population and provide new insight into the current understanding of the etiologies of DSD.

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