Unique three-site compound heterozygous mutation in the WFS1 gene in Wolfram syndrome

Abstract Background Wolfram syndrome (WFS) is a rare autosomal recessive genetic disease whose main cause is mutations in the WFS1 and CISD2 genes. Its characteristic clinical manifestations are diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Methods In this study, two patients from this particular family underwent complete routine biochemical and ophthalmic tests. Blood, urine, routine stool test, visual acuity (VA) examination, visual field assessment, funduscope, optical coherence tomography and periorbital magnetic resonance imaging (MRI) scans were performed for each patient to evaluate whether the nerve fiber layer around the optic nerve head was atrophied and next-generation sequencing of target genes was performed in two patients. Results When the patients were diagnosed with Wolfram syndrome, their genetic analyses suggested unique three-site compound heterozygous mutations (c.2314C > T + c.2194C > T + c.2171C > T) in exon 8 of both patients’ chromosome 4. One mutation (c.2314C > T) was a novel mutation in the known reports of Wolfram syndrome. As a degenerative genetic disease, the types of gene mutations in the Chinese population are generally homozygous mutations at the unit point or compound heterozygous mutations at two nucleotide change sites. However, the two patients reported in this study are the first known cases of compound heterozygous mutations with three mutation sites coexisting on the WFS1 gene in China or even globally. Conclusions This study expands the phenotypic spectrum of Wolfram syndrome and may reveal a novel mutation pattern of pathogenesis of Wolfram syndrome. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with WFS1.

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A Novel Compound Heterozygous Mutation in the WFS1 Gene (C.1997 G>A and C.2113_2114 ins T) Causes wolfram Syndrome: A Case Report

10.21203/rs.3.rs-38184/v1 ◽

2020 ◽

Author(s):

Reyida Aishajiang ◽

Cheng Li ◽

Bo-Tao Shen ◽

Jian Sun ◽

Wei Zhao

Keyword(s):

Case Report ◽

Autosomal Recessive Disorder ◽

Later Life ◽

Wolfram Syndrome ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Sagittal Sinus ◽

Wfs1 Gene ◽

Tract Infections

Abstract Background:Wolfram syndrome (WS) is a rare autosomal recessive disorder associated with early-onset diabetes mellitus (DM), diabetes insipidus (DI), optic atrophy (OA) and hearing impairment. Most patients with WS have mutations in the WFS1 gene, which encodes wolframin. This case report describes a patient with a novel heterozygous mutation of WFS1.Case Presentation:The proband was a 27-year-old Chinese male with WS who had developed DM at the age of 2 years, DI in the first decade, OA, neurogenic bladder and urinary tract infections in the second decade, and neurological abnormalities in later life. Magnetic resonance imaging suggested superior sagittal sinus enlargement and atrophy of the medulla and pons. Sequencing showed that the proband’s asymptomatic parents were both carriers: the father carried a heterozygous c.1997G>A mutation that creates a premature stop at codon 666 (W666X) and that the proband’s asymptomatic mother carried a heterozygous c.2113_2114insT mutation that generates a frameshift downstream to codon 705 (K705Ifs*7) and leads to a stop at codon 711. The proband had both the above C-terminal mutations, resulting in the substitution of N-glycosylation sitesthat are associated with the stability of wolframin.Conclusion:We have identified a novel compound heterozygous mutation of WFS1 that is associated with WS. Our findings may facilitate future screening of WS carriers.

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Hereditary Spherocytosis Caused by a Novel Compound Heterozygous Mutation of the SPTA1 Gene and Autoimmune Hepatitis in a Pediatric Patient

10.21203/rs.3.rs-1023423/v1 ◽

2021 ◽

Author(s):

Yu-mei Qin ◽

Yan-yun Chen ◽

Lin Liao ◽

Yang-yang Wu ◽

Min Chen ◽

...

Keyword(s):

Autoimmune Hepatitis ◽

Hereditary Spherocytosis ◽

Clinical Manifestations ◽

Liver Function Tests ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Concomitant Disease ◽

Genetic Characteristics ◽

Paternal Grandmother

Abstract Objective: Patients suffering from both hereditary spherocytosis (HS) and autoimmune hepatitis (AIH) are very rare. We analyzed the clinical and genetic characteristics of a seven-year-old girl with yellow sclerae and abnormal liver function tests, but no further symptoms. Methods: Blood samples were collected from the proband, her parents, and her paternal grandmother, and analyzed using routine laboratory tests, as well as subjected to next-generation and Sanger sequencing.Results: Compound heterozygous mutations of the spectrin alpha, erythrocytic 1 (SPTA1) gene were identified in the proband. Thec.134G>A (p.R45K) and c.6544G>C (p.D2182H) mutations were inherited from her mother and father, respectively. The proband’s father and paternal grandmother had the same mutation. Neither mutation is described in the Human Gene Mutation Database. Conclusions: HS has clinical manifestations similar to AIH, it may be difficult to diagnose when it coexists with AIH. When laboratory results cannot be explained by autoimmune liver disease alone, the possibility of a concomitant disease should be considered. Pedigree investigation and genetic analyses might be required to arrive at the final diagnosis.

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Novel PTPRQ Mutations Identified in Three Congenital Hearing Loss Patients With Various Types of Hearing Loss

Annals of Otology Rhinology & Laryngology ◽

10.1177/0003489415575041 ◽

2015 ◽

Vol 124 (1_suppl) ◽

pp. 184S-192S ◽

Cited By ~ 8

Author(s):

Naoko Sakuma ◽

Hideaki Moteki ◽

Hela Azaiez ◽

Kevin T. Booth ◽

Masahiro Takahashi ◽

...

Keyword(s):

Hearing Loss ◽

Clinical Manifestations ◽

Vestibular Dysfunction ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Caloric Test ◽

Compound Heterozygous ◽

Site Mutation ◽

Vestibular Evoked Myogenic Potential ◽

Phenotypic Features

Objectives: We present 3 patients with congenital sensorineural hearing loss (SNHL) caused by novel PTPRQ mutations, including clinical manifestations and phenotypic features. Methods: Two hundred twenty (220) Japanese subjects with SNHL from unrelated and nonconsanguineous families were enrolled in the study. Targeted genomic enrichment with massively parallel DNA sequencing of all known nonsyndromic hearing loss genes was performed to identify the genetic cause of hearing loss. Results: Four novel causative PTPRQ mutations were identified in 3 cases. Case 1 had progressive profound SNHL with a homozygous nonsense mutation. Case 2 had nonprogressive profound SNHL with a compound heterozygous mutation (nonsense and missense mutation). Case 3 had nonprogressive moderate SNHL with a compound heterozygous mutation (missense and splice site mutation). Caloric test and vestibular evoked myogenic potential (VEMP) test showed vestibular dysfunction in Case 1. Conclusion: Hearing loss levels and progression among the present cases were varied, and there seem to be no obvious correlations between genotypes and the phenotypic features of their hearing loss. The PTPRQ mutations appeared to be responsible for vestibular dysfunction.

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New Compound Heterozygous Mutations of GPIIb in Patient with Glanzmann Thrombasthenia.

Blood ◽

10.1182/blood.v110.11.3921.3921 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3921-3921

Author(s):

Ziqiang Yu ◽

Jian Su ◽

Xia Bai ◽

Zhaoyue Wang ◽

Changgeng Ruan

Keyword(s):

Flow Cytometry ◽

Autosomal Recessive ◽

Protein Translation ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Sequencing Analysis ◽

Glanzmann Thrombasthenia ◽

Compound Heterozygous Mutations ◽

Average Fluorescence

Abstract Glanzmann thrombasthenia (GT) is a homozygous or compound heterozygous autosomal recessive bleeding disorder caused by the qualitative or quantitative deficiency of integrin GPIIb-IIIa, which acts as the receptor of platelet fibrinogen. Here we report a case of GT with a compound heterozygous mutation in GPIIb according to the results of flow cytometry and genetic investigation.The flow cytometry was used to measure the average amounts of integrin GPIIb-IIIa on the patient’s platelets, and all 30 exons of GPIIb were amplified and sequenced with the corresponding primers.The average fluorescence intensity of integrin GPIIb-IIIa were 3.07 and 12.5, respectively, compared with 23.7 and 254, respectively, in the normal healthy individuals. And sequencing analysis of all exons of GPIIb demonstrated that there existed following compound heterozygous mutations in GPIIb gene: one heterozygote mutation (68 C→A) in the 1st exon, which resulted in Pro 23 His substitution in signal peptide domain; one nonsense heterozygous mutation (1750 C→T) in the 17th exon, which result in premature termination; one heterozygote mutation (2159 T→C) in the 21stexon, which resulted in Leu 720 Pro substitution. According to Glanzmann thrombasthenia database of ISTH (http://sinaicentral.mssm.edu/intranet/research/glanzmann/listmutations?mut=GPIIb), 68 C→A mutation and 2159 T→C mutation are novel mutations in the GPIIb heavy chain. These compound heterozygous mutations in GPIIb gene might be a novel pathogenetic mechanism of GT, which impaired the protein translation and co-expression with GPIIIa on the membrane of platelet.

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Immunodeficiency and severe gastrointestinal manifestations in a patient with novel DKC1 mutations causing Hoyeraal–Hreidarsson syndrome

LymphoSign Journal ◽

10.14785/lymphosign-2016-0006 ◽

2016 ◽

Vol 3 (3) ◽

pp. 119-126 ◽

Cited By ~ 1

Author(s):

Nufar Marcus

Keyword(s):

Case Report ◽

Cell Function ◽

Novel Mutation ◽

Severe Combined Immunodeficiency ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Combined Immunodeficiency ◽

Gastrointestinal Manifestations ◽

Over Time

Background: Hoyeraal–Hreidarsson syndrome (HHS) is considered a clinically severe variant of dyskeratosis congenita (DKC) and represents the extreme phenotype caused by aberrant telomere biology. Unlike patients with DKC who present later in life, most cases of HHS present in the first years of life. Clinical features include intrauterine growth restriction and microcephaly, which are universal but not pathognomonic, as well as gastrointestinal, immunological and neurological manifestations. The immunological profile is varied as a result of cellular immunodeficiency, humoral defects, or both, and may be the presenting symptom of these patients. Moreover, the immunological phenotype can change over time, making HHS a diagnostic challenge. Methods: This case report highlights the clinical presentation and immune investigations of a male patient with a novel mutation in DKC1, causing HHS. Results: Here, we describe a patient with HHS who presented with Pneumocystis jiroveci pneumonia and low T cells, which is typical of severe combined immunodeficiency. Over time, he developed agammaglobulinemia whereas T-cell function improved. He also presented with extremely severe gastrointestinal manifestations, and died at 3 years of age. Conclusion: This case report highlights a novel compound heterozygous mutation in DKC1, and the need to consider HHS as the differential diagnosis of patients with combined immunodeficiency. Statement of novelty: The case reports on a novel mutation in DKC1.

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Hepatic Manifestations of 3-Hydroxy-3-Methylglutaryl-Coenzyme-A Lyase Deficiency in Saudi Patients: Experience of a Tertiary Care Center

Journal of Pediatric Genetics ◽

10.1055/s-0040-1714698 ◽

2020 ◽

Author(s):

Sinan Holdar ◽

Zuhair Rahbeeni ◽

Khushnooda Ramzan ◽

Faiqa Imtiaz

Keyword(s):

Coenzyme A ◽

Care Center ◽

Tertiary Care ◽

Clinical Manifestations ◽

Research Centre ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Laboratory Findings ◽

Saudi Patients

Abstract3-Hydroxy-3-methylglutaryl-coenzyme-A lyase (HMGCL) deficiency, a rare autosomal recessive disorder, is caused by a homozygous or compound heterozygous mutation in the HMGCL gene (chromosome 1p36.11). HMGCL catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Several studies have reported general hepatic findings (e.g., hepatomegaly) in patients with HMGCL deficiency, but currently, there are no available data regarding the incidence and epidemiology of liver involvement. The main objective of our study was to investigate the overall clinical manifestations, laboratory findings, genotype, and presence of hepatic involvement in Saudi patients with HMGCL deficiency. A retrospective chart review of patients with HMGCL deficiency including those with a documented hepatic manifestation was performed at the King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia. We evaluated 50 cases of HMGCL deficiency. Hepatic findings were found in 17 patients at the time of diagnosis. The mean age of hepatic presentation was 135 days, and the median age was 56 days (range: 2–315 days). Hepatomegaly was found in 65%, abnormal biochemical profile in 47%, and an abnormal imaging in 53% of patients. The most frequent mutation in this cohort was the p.Arg41Gln founder mutation (59%). In comparison to data from the current literature, HMGCL deficiency can be considered as a diagnostic metabolite for hepatic manifestations and requires appropriate evaluation, including molecular genetic analysis.

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Hereditary intrinsic factor deficiency in China caused by a novel mutation in the intrinsic factor gene—a case report

BMC Medical Genetics ◽

10.1186/s12881-020-01158-z ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Jing Ruan ◽

Bing Han ◽

Junling Zhuang ◽

Miao Chen ◽

Fangfei Chen ◽

...

Keyword(s):

Novel Mutation ◽

Intrinsic Factor ◽

Chinese Patient ◽

Cobalamin Deficiency ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Indirect Bilirubin ◽

Factor Deficiency ◽

Intrinsic Factor Deficiency

Abstract Background Hereditary intrinsic factor deficiency is a rare disease characterized by cobalamin deficiency with the lack of gastric intrinsic factor because of gastric intrinsic factor (GIF) mutations. Patients usually present with cobalamin deficiency without gastroscopy abnormality and intrinsic factor antibodies. Case presentation A Chinese patient presented with recurrent severe anemia since age 2 with low cobalamin level and a mild elevation of indirect bilirubin. The hemoglobin level normalized each time after intramuscular vitamin B12 injection. Gene test verified a c.776delA frame shift mutation in exon 6 combined with c.585C > A nonsense early termination mutation in exon 5 of GIF which result in the dysfunction of gastric intrinsic factor protein. The hereditary intrinsic factor deficiency in literature was further reviewed and the ancestry of different mutation sites were discussed. Conclusions A novel compound heterozygous mutation of GIF in a Chinese patient of hereditary intrinsic factor deficiency was reported. It was the first identified mutation of GIF in East-Asia and may indicate a new ancestry.

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A Novel Compound Heterozygous Mutation of FSHR Causes Primary Ovarian Insufficiency

10.21203/rs.3.rs-64914/v1 ◽

2020 ◽

Author(s):

Nan Zhang ◽

Jiawei Xu ◽

Xiao Bao ◽

Feifei Zhao ◽

Dayuan Shi ◽

...

Keyword(s):

Novel Mutation ◽

Primary Ovarian Insufficiency ◽

Compound Heterozygous Mutation ◽

Chinese Family ◽

Heterozygous Mutation ◽

Primary Amenorrhea ◽

Compound Heterozygous ◽

Ovarian Insufficiency ◽

Functional Analyses

Abstract Background: Primary ovarian insufficiency, one of the main causes of female infertility, is a heterogeneous disease when it comes to the phenotype and etiology. Familial cases are observed in approximately 10% of patients which indicates a strong genetic component. However, the underlying cause remains to be identified in most cases of patients.Methods: Here we studied an un-consanguineous Han Chinese family in which four siblings are primary amenorrhea and hypergonadotropic hypogonadism. Three siblings with POI and one unaffected sibling were exome sequenced. Also, other members in this family were genotyped by Sanger Sequencing. In silicon and in-vitro functional analyses were performed.Results: Whole exome sequencing identified a shared novel compound heterozygous mutation of FSHR gene in all the affected members. c.1412T>G, the first variant identified in FSHR IL2(intracellular loop2) in POI patients, and another novel mutation c.1090_1091del were the genetic etiology of this family. In-vitro functional analyses showed that cAMP (second messenger of FSHR) producing was abolished by c.1412T>G. Conclusions: Our study identified two novel FSHR mutations in a compound heterozygous state and gave the evidence that the FSHR IL2 could play a crucial role in FSHR-caused POI.

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Novel mutation in the CHST14 gene causing musculocontractural type of Ehlers-Danlos syndrome

BMJ Case Reports ◽

10.1136/bcr-2018-226165 ◽

2018 ◽

pp. bcr-2018-226165 ◽

Cited By ~ 2

Author(s):

Sapna Sandal ◽

Anupriya Kaur ◽

Inusha Panigrahi

Keyword(s):

Connective Tissue ◽

Novel Mutation ◽

Connective Tissue Disorder ◽

Rare Disorder ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Bleeding Tendency ◽

Ehlers Danlos Syndrome ◽

Danlos Syndrome

Musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) is a recently recognised connective tissue disorder. MC-EDS is caused by homozygous or compound heterozygous mutation in the carbohydrate sulfotransferase 14 (CHST14) gene on chromosome 15q15. Herein, we report a case of a 3-year-old boy with MC-EDS in whom a novel mutation in the CHST14 gene was discovered. Besides being the second report of this rare disorder from India, the child till 3 years has not had any bleeding tendency as described in the earlier reports of this disorder.

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The genetics and clinical manifestations of patients with vitamin D dependent rickets type 1A

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0691 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Ayse Ozden ◽

Hakan Doneray

Keyword(s):

Vitamin D ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Treatment Modalities ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Laboratory Findings ◽

Day Range ◽

The Mean

Abstract Objectives Vitamin D dependent rickets type 1A (VDDR-1A) is a very rare autosomal recessive disorder caused by mutations in the CYP27B1, which encodes vitamin D 1α-hydroxylase. We report the genetics and clinical manifestations of nine patients with VDDR-1A and compare our patients to other cases with the same mutations in the literature. Methods The clinical presentations, clinical and laboratory findings and treatment modalities of the patients were evaluated retrospectively. Results The mean age of the patients at the time of diagnosis was 39.9 months (range: 4.5–111). At the time of diagnosis, six patients had received stoss vitamin D therapy. Clinical findings related to rickets were obvious in seven patients and unclear in two patients. Except for one case, all patients had laboratory findings of rickets. A novel variant and four previously reported mutations in CYP27B1 were identified. The mean calcitriol and elemental calcium dose were 45.5 ng/kg/day (range: 20–70) and 75.6 mg/kg/day (range: 45–125), respectively. Conclusions We found a novel compound heterozygous mutation consisting of a reported duplication [(p.F443Pfs*24 (c.1319_1325 dup CCCACCC)] in exon 8 and a novel deletion [p.D507Efs*34 (c.1521 delC)] in exon 9. Our study suggests that the clinical manifestations and laboratory findings of the patients with VDDR1A are variable even among the patients with the same mutation.

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