A Novel Missense Variant of TP63 Heterozygously Present in Split-Hand/Foot Malformation

Background. Split-hand/foot malformation (SHFM) is a severe congenital disability mainly characterized by the absence or hypoplasia of the central ray of the hand/foot. To date, several candidate genes associated with SHFM have been identified, including TP63, DLX5, DLX6, FGFR1, and WNT10B. Herein, we report a novel variant of TP63 heterozygously present in affected members of a family with SHFM. Methods. This study investigated a Chinese family, in which the proband and his son suffered from SHFM. The peripheral blood sample of the proband was used to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Postsequencing bioinformatic analyses and Sanger sequencing were conducted to verify the identified variants and parental origins on all family members in the pedigree. Results. By postsequencing bioinformatic analyses and Sanger sequencing, we identified a novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in this family that results in a substitution of methionine with isoleucine, which is probably associated with the occurrence of SHFM. Conclusion. A novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in SHFM was thus identified, which may enlarge the spectrum of known TP63 variants and also provide new approaches for genetic counselling of families with SHFM.

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Whole exome sequencing of a family revealed a novel variant in the CHM gene, c.22delG p.(Glu8Serfs*4), which co-segregated with choroideremia

Bioscience Reports ◽

10.1042/bsr20200067 ◽

2020 ◽

Vol 40 (5) ◽

Author(s):

Handong Dan ◽

Tuo Li ◽

Xinlan Lei ◽

Xin Huang ◽

Yiqiao Xing ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Family Members ◽

Clinical Manifestations ◽

Complex Form ◽

Chinese Family ◽

Sequencing Data ◽

Whole Exome ◽

Novel Variant

Abstract Choroideremia is a complex form of blindness-causing retinal degeneration. The aim of the present study was to investigate the pathogenic variant and molecular etiology associated with choroideremia in a Chinese family. All available family members underwent detailed ophthalmological examinations. Whole exome sequencing, bioinformatics analysis, Sanger sequencing, and co-segregation analysis of family members were used to validate sequencing data and confirm the presence of the disease-causing gene variant. The proband was diagnosed with choroideremia on the basis of clinical manifestations. Whole exome sequencing showed that the proband had a hemizygous variant in the CHM gene, c.22delG p. (Glu8Serfs*4), which was confirmed by Sanger sequencing and found to co-segregate with choroideremia. The variant was classified as likely pathogenic and has not previously been described. These results expand the spectrum of variants in the CHM gene, thus potentially enriching the understanding of the molecular basis of choroideremia. Moreover, they may provide insight for future choroideremia diagnosis and gene therapy.

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A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/eje-16-0968 ◽

2017 ◽

Vol 176 (5) ◽

pp. K9-K14 ◽

Cited By ~ 5

Author(s):

Sandrine Caburet ◽

Ronit Beck Fruchter ◽

Bérangère Legois ◽

Marc Fellous ◽

Stavit Shalev ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Polycystic Ovary ◽

Missense Variant ◽

Genetic Alterations ◽

Homozygous Mutation ◽

Gonadotropin Secretion ◽

Whole Exome ◽

A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

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Whole-Genome Linkage Analysis with Whole-Exome Sequencing Identifies a Novel Frameshift Variant in NEFH in a Chinese Family with Charcot-Marie-Tooth 2: A Novel Variant in NEFH for Charcot-Marie-Tooth 2

Neurodegenerative Diseases ◽

10.1159/000487754 ◽

2018 ◽

Vol 18 (2-3) ◽

pp. 74-83 ◽

Cited By ~ 1

Author(s):

Xianli Bian ◽

Pengfei Lin ◽

Jiangxia Li ◽

Feng Long ◽

Ruonan Duan ◽

...

Keyword(s):

Linkage Analysis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chinese Family ◽

Whole Genome ◽

Charcot Marie Tooth ◽

Whole Exome ◽

Novel Variant

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Identification of a Heterozygous Mutation in the TGFBI Gene in a Hui-Chinese Family with Corneal Dystrophy

Journal of Ophthalmology ◽

10.1155/2019/2824179 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Qin Xiang ◽

Lamei Yuan ◽

Yanna Cao ◽

Hongbo Xu ◽

Yunfeiyang Li ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Transforming Growth Factor ◽

Corneal Dystrophy ◽

Chinese Family ◽

Heterozygous Mutation ◽

Type I ◽

Whole Exome ◽

The Family

Background/Aims. Corneal dystrophies (CDs) belong to a group of hereditary heterogeneous corneal diseases which result in visual impairment due to the progressive accumulation of deposits in different corneal layers. So far, mutations in several genes have been responsible for various CDs. The purpose of this study is to identify gene mutations in a three-generation Hui-Chinese family associated with granular corneal dystrophy type I (GCD1). Methods. A three-generation Hui-Chinese pedigree with GCD1 was recruited for this study. Slit-lamp biomicroscopy, optical coherence tomography, and confocal microscopy were performed to determine the clinical features of available members. Whole exome sequencing was performed on two patients to screen for potential disease-causing variants in the family. Sanger sequencing was used to test the variant in the family members. Results. Clinical examinations demonstrated bilaterally abundant multiple grayish-white opacities in the basal epithelial and superficial stroma layers of corneas of the two patients. Whole exome sequencing revealed that a heterozygous missense mutation (c.1663C > T, p.Arg555Trp) in the transforming growth factor beta-induced gene (TGFBI) was shared by the two patients, and it cosegregated with this disease in the family confirmed by Sanger sequencing. Conclusions. The results suggested that the heterozygous TGFBI c.1663C > T (p.Arg555Trp) mutation was responsible for GCD1 in the Hui-Chinese family, which should be of great help in genetic counseling for this family.

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A Novel BBS9 Mutation Identified via Whole-Exome Sequencing in a Chinese Family with Bardet-Biedl Syndrome

BioMed Research International ◽

10.1155/2021/4514967 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Yue Zhang ◽

Manhong Xu ◽

Minglian Zhang ◽

Guoxing Yang ◽

Xiaorong Li

Keyword(s):

Mental Retardation ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Chinese Family ◽

Cone Dystrophy ◽

Bardet Biedl Syndrome ◽

Homozygous Variant ◽

Whole Exome

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by polydactyly, obesity, rod-cone dystrophy, and mental retardation. Twenty-one genes have been identified as causing BBS. This study collected a BBS pedigree from two patients and performed whole-exome sequencing on one patient. We identified a novel homozygous variant c.1114C>T (p.Q372X) in the BBS9 of the two siblings. This variant was confirmed and completely cosegregated with the disease of this family by Sanger sequencing. We report a novel homozygous variant c.1114C>T in the BBS9 gene in a Chinese family.

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Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss

BMC Medical Genomics ◽

10.1186/s12920-021-00871-9 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Guangxian Yang ◽

Yi Yin ◽

Zhiping Tan ◽

Jian Liu ◽

Xicheng Deng ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Chinese Family ◽

Heterozygous Mutation ◽

Homozygous Mutation ◽

Nonsyndromic Hearing Loss ◽

Whole Exome ◽

Renal Malformations

Abstract Background Previous studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns. Methods A Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss. Results Via whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis. Conclusions This study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

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Whole Exome Sequencing Revealed a Novel Sequence Variant in The OTULIN Underlying Auto-Inflammatory Syndrome

10.21203/rs.3.rs-164929/v1 ◽

2021 ◽

Author(s):

Rubab Raza ◽

Raul Jimenez-Heredia ◽

Muhammad Zeeshan Anwar ◽

Asmat Ullah ◽

Ayisha Zia ◽

...

Keyword(s):

Flow Cytometry ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

In Silico ◽

Sanger Sequencing ◽

Inflammatory Diseases ◽

Missense Variant ◽

Sequence Variant ◽

Whole Exome ◽

Inflammatory Syndrome

Abstract Purpose Systemic auto-inflammatory diseases are a diverse group of heterogeneous disorders resulting in development of the systemic inflammation in absence of the inflammatory induction. Sequence variants in the OTULIN gene, which disrupts its ubiquitination activity lead to auto-inflammation, panniculitis, and dermatosis syndrome. To date, only few disease-causing variants in the OTULIN have been reported.In the study, presented here, sequence analysis of the OTULIN gene in a patient, exhibiting features of OTULIN-related auto-inflammatory syndrome (ORAS), revealed a novel disease-causing missense variant p.(Thr312Met). Further, effect of the variant on structure and function of the OTULIN protein has been examined using in silico OTULINWT and OTULINT312M. Methods Cells, collected from the patient blood, were examined by flow cytometry. Search for the disease-causing variants was carried out using exome followed by Sanger sequencing. Effect of the sequence variant on structure of the mutated protein was studied using in-silico analyses. Results Flow cytometry analysis revealed slightly reduced number of lymphocytes, marked leukocytosis, and mildly increased levels of IgG. Whole exome sequencing coupled with Sanger sequencing revealed a homozygous missense variant [c.935C>T; p.(Thr312Met)] in the OTULIN gene. In-silico analyses revealed that the missense variant reduces OTULIN’s expression and promotes accumulation of LUBAC-linked UB chains leading to auto-inflammation.Conclusion Taken together, OTULIN may act as a novel therapeutic target for the development of immunomodulatory drugs that may potentially increase or stabilize their expression. Targeting more components of the Ub-proteasome pathway may provide new opportunities for therapeutic exploitation and drug discovery.

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Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease

Bioscience Reports ◽

10.1042/bsr20180872 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 2

Author(s):

Qin Xiang ◽

Yanna Cao ◽

Hongbo Xu ◽

Yi Guo ◽

Zhijian Yang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Retinal Pigment ◽

Han Chinese ◽

Chinese Family ◽

Compound Heterozygous ◽

Stargardt Disease ◽

Pathogenic Variants ◽

Whole Exome

Abstract Stargardt disease (STGD1, OMIM 248200) is a common hereditary juvenile or early adult onset macular degeneration. It ultimately leads to progressive central vision loss. Here, we sought to identify gene mutations associated with STGD1 in a three-generation Han Chinese pedigree by whole exome sequencing and Sanger sequencing. Two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in the ATP binding cassette subfamily A member 4 gene (ABCA4) were identified as contributing to the family’s STGD1 phenotype. These variants may impact the ABCA4 protein structure and reduce the retinal-activated ATPase activity, leading to abnormal all-trans retinal accumulation in photoreceptor outer segments and in retinal pigment epithelium cells. The present study broadens the mutational spectrum of the ABCA4 responsible for STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1.

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Whole Exome Sequencing in Early-onset Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.171358 ◽

2018 ◽

Vol 45 (12) ◽

pp. 1671-1679 ◽

Cited By ~ 5

Author(s):

Ezgi Deniz Batu ◽

Can Koşukcu ◽

Ekim Taşkıran ◽

Sezgin Sahin ◽

Sema Akman ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Lupus Erythematosus ◽

Early Onset ◽

Sanger Sequencing ◽

Systemic Lupus ◽

Whole Exome ◽

Novel Variant ◽

Missense Alteration

Objective.Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder. Early-onset, familial, and/or syndromic SLE may reveal monogenic pathologies. The aim of this study was to examine genetic associations in patients with early-onset or familial SLE.Methods.We enrolled 7 SLE cases (from different families) with disease onset ≤ 5 years of age and family history consistent with an autosomal recessive inheritance. Whole exome sequencing (WES) was performed in 6 index cases. Suspected variants were confirmed by Sanger sequencing. We did not perform WES in 1 patient who had features similar to the first 3 cases; only the exons of C1QA, C1QB, and C1QC were screened with Sanger sequencing.Results.We demonstrated 2 novel and 3 previously reported variants in genes associated with SLE: a homozygous non-sense alteration (c.622C>T/p.Gln208Ter) in C1QA in 2 patients; homozygous non-sense alteration (c.79C>T/p.Gln27Ter) in C1QC in 1 (novel variant); homozygous missense alteration (c.100G>A/p.Gly34Arg) in C1QC in 1; homozygous missense alteration (c.1945G>C/p.Ala649Pro) in C1S in 1 (novel variant); and homozygous frameshift alteration (c.289_290delAC/p.Thr97Ilefs*2) in DNASE1L3 in 1 patient. Further, in 1 patient, we determined a strong candidate variant in HDAC7 (histone decetylase 7).Conclusion.Five patients had homozygous alterations in genes coding early complement proteins. This may lead to decreased clearance of apoptotic bodies. One patient had DNASE1L3 variant, which functions in the clearance of self-antigens. In 1 patient, we determined a novel gene that may be important in SLE pathogenesis. We suggest that monogenic causes/associations should be sought in early-onset and/or familial SLE.

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