scholarly journals MITF p.Arg217Thr Variant Identified in a Han Chinese Family with Tietz/Waardenburg Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Rong Yu ◽  
Lv Liu ◽  
Ya-Li Li ◽  
Liang-Liang Fan
Keyword(s):  
Hearing Loss ◽  
Genetic Disorders ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Han Chinese ◽  
White Hair ◽  
Chinese Family ◽  
Waardenburg Syndrome ◽  
Genetic Lesion

Waardenburg syndrome (WS) is a group of rare genetic disorders characterized by hearing loss, changes in coloring of hair, skin, and eyes, and alterations in the shape of the face. Tietz syndrome is another rare disorder which presented similar phenotypes to WS. Patients with Tietz/Waardenburg syndrome often present with pale blue eyes, albino skin, and distinctive hair coloring, such as a patch of white hair or hair that prematurely turns gray. At present, more than six candidate genes are responsible for four types of Waardenburg syndrome and Tietz syndrome. This study is aimed at identifying the pathogenic gene variants in a three-generation Han Chinese family with hearing loss, blue-gray iris, albino skin, and white hair. In order to discover the molecular genetic lesion underlying the disease phenotype, whole exome sequencing in the proband, with Tietz/Waardenburg syndrome phenotypes, of a Han Chinese family from HeBei, China, was conducted. A novel heterozygous c.650G>C/p.Arg217Thr variant in melanocyte inducing transcription factor (MITF) was identified. Sanger sequencing further validated that this mutation existed in three affected individuals and absent in healthy family members. Bioinformatics analysis predicted that this mutation was deleterious. Our study further identified the genetic lesion of the family. Simultaneously, our study may also contribute to genetic counseling, embryonic screening of in vitro fertilized embryos, and prenatal genetic diagnosis of patients with Tietz/Waardenburg syndrome, especially for the proband, unmarried and unpregnant women, to reduce familial transmission in this Han Chinese family.

scholarly journals Identification of an unknown frameshift variant of NOG in a Han Chinese family with proximal symphalangism

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhuang-Zhuang Yuan ◽  
Fang Yu ◽  
Jie-Yuan Jin ◽  
Zi-Jun Jiao ◽  
Ju-Yu Tang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Conductive Hearing Loss ◽  
Genetic Diagnosis ◽  
Chinese Patient ◽  
Chinese Family ◽  
Autosomal Dominant Disorder ◽  
Genetic Lesion ◽  
Whole Exome ◽  
The Family ◽  
Conductive Hearing

Abstract Proximal symphalangism (SYM1) is an autosomal dominant disorder manifested by ankylosis of the proximal interphalangeal joints of fingers, carpal and tarsal bone fusion, and conductive hearing loss in some cases. Herein, we clinically diagnosed a Chinese patient with fusions of the bilateral proximal interphalangeal joints in the 2–5 digits without conductive hearing loss. Family history investigation revealed that his mother and grandfather also suffered from SYM1. Whole exome sequencing was performed to detect the genetic lesion of the family. The candidate gene variants were validated by Sanger sequencing. By data filtering, co-segregation analysis and bioinformatics analysis, we highly suspected that an unknown heterozygous frameshift variant (c.635_636insG, p.Q213Pfs*57) in NOG was responsible for the SYM1 in the family. This variant was predicted to be deleterious and resulted in a prolonged protein. This finding broadened the spectrum of NOG mutations associated with SYM1 and contributed to genetic diagnosis and counseling of families with SYM1.

Maternally inherited hearing loss is associated with the novel mitochondrial tRNASer(UCN) 7505T>C mutation in a Han Chinese family

2010 ◽  
Vol 100 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Xiaowen Tang ◽  
Ronghua Li ◽  
Jing Zheng ◽  
Qin Cai ◽  
Ting Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Han Chinese ◽  
Chinese Family ◽  
The Novel

316 GENOMIC EVALUATION OF BOVINE EMBRYOS WITHIN 24 HOURS

2015 ◽  
Vol 27 (1) ◽  
pp. 247
Author(s):  
S. Jung ◽  
M. Reichenbach ◽  
R. Fries ◽  
E. Wolf ◽  
C. Gschoederer ◽  
...  
Keyword(s):  
Genetic Disorders ◽  
Molecular Genetic ◽  
Diploid Cell ◽  
Bovine Embryos ◽  
Genomic Evaluation ◽  
Dna Amount ◽  
Embryo Recovery ◽  
Male Subfertility ◽  
And Gender

The aim of this study was to develop a reliable procedure for genomic evaluation of bovine embryos to determine gender, polled status, and hereditary defects within 24 h after collection. German Simmental animals (n = 15) were superovulated (n = 25) using a standard protocol. Embryos were recovered on Day 7 (Day 0 = oestrus). A total of 217 embryos (morula, n = 130; early blastocyst, n = 43; blastocyst, n = 44) were biopsied with a steel blade attached to a micromanipulator. Biopsied cells were immediately transferred into 1 µL TE buffer to a 500 µL reaction tube and embryos were in vitro cultured until genomic results were available. For commonly used molecular genetic methods (e.g. 5′-exonuclease genotyping, PCR or high density genotyping) DNA amounts of 2–200 ng are required. However, the DNA quantity of a single diploid cell amounts to 6 pg only. The embryo biopsies used, usually consists of 10–30 cells, necessitating an artificial amplification of the embryonic genome. Taking all vital measures to avoid external DNA contamination, isothermal whole genome amplification was performed with the REPLI-g Mini Kit (Qiagen, Valencia, CA, USA) using random hexamers and Phi29-Polymerase. Depending on the number of cells, a total DNA amount of 4–7 µg was achieved. Polled status and gender was determined using PCR with subsequent gel-electrophoresis. 5′-exonuclease assays were used to obtain genotypes for the detection of genetic defects. At present, eight, mostly Simmental-specific genetic disorders can be examined: three traits associated with severe growth retardation, dwarfism (DW), Braunvieh-haplotype 2 (BH2) and stunted growth (FH2), the lethal skin disorder zinc deficiency-like syndrome (ZDL), a fertility trait bovine male subfertility (BMS), embryonic death Fleckvieh-haplotype 4 (FH4), a bleeding disorder thrombopathia (TP) and arachnomelia (A), within 24 h. On average, 8.7 embryos were biopsied per embryo recovery, i.e. 93.9% of the total number of transferable embryos. Fourteen embryo samples (6.5%) totally failed during analysis, possibly due to the loss of samples. In successful analyses, gender was undetermined in two embryos; remaining embryos were 52.2% female and 47.8% male. Polled status could be analysed in 92.6% of the embryos. The analyses of embryos for possible inherited genetic disorders (healthy, heterozygote, or homozygote; n = 578) were successful in 90.1%. The transfer of biopsied embryos (n = 30) led to 63.3% pregnancies (Day 42). A validation of the present results has to be done as soon as the produced calves are born, demonstrating the reliability of the procedure.Research was funded by the Bayerische Forschungsstiftung (AZ-1031-12).

scholarly journals Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis

Blood ◽  
2020 ◽  
Vol 136 (17) ◽  
pp. 1933-1945
Author(s):  
Emese Molnár ◽  
Nesrine Radwan ◽  
Gábor Kovács ◽  
Hajnalka Andrikovics ◽  
Frances Henriquez ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Molecular Genetic ◽  
Group Identification ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Functional Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Lymphoproliferative Syndrome

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficiency caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, CASP10). This study evaluated the clinical manifestations, laboratory findings, and molecular genetic results of 215 patients referred as possibly having ALPS. Double-negative T-cell (DNT) percentage and in vitro apoptosis functional tests were evaluated by fluorescence-activated cell sorting; interleukin 10 (IL-10) and IL-18 and soluble FAS ligand (sFASL) were measured by enzyme-linked immunosorbent assay. Genetic analysis was performed by next-generation sequencing. Clinical background data were collected from patients’ records. Patients were categorized into definite, suspected, or unlikely ALPS groups, and laboratory parameters were compared among these groups. Of 215 patients, 38 met the criteria for definite ALPS and 17 for suspected ALPS. The definite and suspected ALPS patient populations showed higher DNT percentages than unlikely ALPS and had higher rates of lymphoproliferation. Definite ALPS patients had a significantly more abnormal in vitro apoptosis function, with lower annexin, than patients with suspected ALPS (P = .002) and patients not meeting ALPS criteria (P < .001). The combination of elevated DNTs and an abnormal in vitro apoptosis functional test was the most useful in identifying all types of ALPS patients; the combination of an abnormal in vitro apoptosis functional test and elevated sFASLs was a predictive marker for ALPS-FAS group identification. Lymphoproliferation, apoptosis functional test, and DNTs are the most sensitive markers; elevated IL-10 and IL-18 are additional indicators for ALPS. The combination of elevated sFASLs and abnormal apoptosis function was the most valuable prognosticator for patients with FAS mutations.

scholarly journals The mitochondrial COI/tRNASER(UCN) G7444A mutation may be associated with hearing impairment in a Han Chinese family

2017 ◽  
Vol 20 (2) ◽  
pp. 43-49
Author(s):  
Y Ding ◽  
B-H Xia ◽  
Y-S Teng ◽  
G-C Zhuo ◽  
J-H Leng
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Genome ◽  
Age At Onset ◽  
Han Chinese ◽  
Pathogenic Variant ◽  
Chinese Family ◽  
12S Rrna ◽  
Pathogenic Variants ◽  
Functional Variants ◽  
High Penetrance

Abstract Variations in mitochondrial genome have been found to be associated with hearing loss. Of these, the mitochondrial 12S rRNA and tRNASer(UCN) are the hot-spots for pathogenic variants associated with deafness. To understand the putative role of mitochondrial DNA (mtDNA) variants in hearing loss, we recently screened the variants in mitochondrial genomes in patients with deafness from the Hangzhou area of Zhejiang Province, People’s Republic of China (PRC). In this study, we describe a maternally-inherited Han Chinese family with high penetrance of hearing loss, notably, the penetrance of hearing loss in this family were 80.0 and 40.0%, when the aminoglycoside was included or excluded. Three matrilineal relatives in this pedigree exhibited different levels of hearing loss with different age at onset. In addition, sequence analysis of the complete mitochondrial genome showed the presence of the well-known C1494T pathogenic variant in the 12S rRNA gene and the G7444A pathogenic variant in the COI/ tRNASer(UCN). The C1494T anomaly had been reported to be a pathogenic mutation associated with aminoglycoside-induced and nonsyndromic hearing loss (AINHL), while the G7444A was considered as a secondary mutation associated with deafness. However, the lack of functional variants in GJB2 and TRMU genes suggested that nuclear modified genes may not play important roles in deafness expression. Thus, the combination of G7444A and C1494T pathogenic variants in the mitochondrial genome may account for the high penetrance of hearing loss in this Chinese family.

scholarly journals Interpreting TMEM67 missense variants of uncertain significance (VUS) in an animal model

2021 ◽  
Author(s):  
Karen I Lange ◽  
Sunayna Best ◽  
Sofia Tsiropoulou ◽  
Ian Berry ◽  
Colin A Johnson ◽  
...  
Keyword(s):  
Animal Model ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Knock Out ◽  
Variants Of Uncertain Significance ◽  
C Elegans ◽  
In Vivo Animal Model ◽  
Uncertain Significance

Purpose: A molecular genetic diagnosis is essential for accurate counselling and management of patients with ciliopathies. Uncharacterized missense alleles are often classified as variants of uncertain significance (VUS) and are not clinically useful. In this study, we explore the use of a tractable animal model (C. elegans) for in vivo interpretation of missense VUS alleles of TMEM67, a gene frequently mutated as a cause of ciliopathies. Methods: CRISPR/Cas9 gene editing was used to generate homozygous worm strains carrying TMEM67 patient variants. Quantitative phenotypic assays (dye filling, roaming, chemotaxis) assessed cilia structure and function. Results were validated by genetic complementation assays in a human TMEM67 knock-out hTERT-RPE1 cell line. Results: Quantitative assays in C. elegans distinguished between known benign (Asp359Glu, Thr360Ala) and pathogenic (Glu361Ter, Gln376Pro) variants. Analysis of seven missense VUS alleles predicted two benign (Cys173Arg, Thr176Ile) and four pathogenic variants (Cys170Tyr, His782Arg, Gly786Glu, His790Arg). Results from one VUS (Gly979Arg) were inconclusive in worms, but additional in vitro validation suggested it was likely benign. Conclusion: Efficient genome editing and quantitative functional assays in C. elegans make it a tractable in vivo animal model that allows stratification and rapid, cost-effective interpretation of ciliopathy-associated missense VUS alleles.

A COL4A5 Missense Variant in a Han-Chinese Family with X-linked Alport Syndrome

2019 ◽  
Vol 19 (10) ◽  
pp. 758-765
Author(s):  
Yuan Wu ◽  
Yi Guo ◽  
Jinzhong Yuan ◽  
Hongbo Xu ◽  
Yong Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sanger Sequencing ◽  
Alport Syndrome ◽  
Genetic Defect ◽  
Missense Variant ◽  
Han Chinese ◽  
Chinese Family ◽  
Chain Gene ◽  
Renal Disorder ◽  
The Family

Background: Alport syndrome (AS) is an inherited familial nephropathy, characterized by progressive hematuric nephritis, bilateral sensorineural hypoacusis and ocular abnormalities. X-linked AS (XLAS) is the major AS form and is clinically heterogeneous, and it is associated with defects in the collagen type IV alpha 5 chain gene (COL4A5). Objective: The purpose of this research is to detect the genetic defect responsible for renal disorder in a 3-generation Han-Chinese pedigree. Methods: Detailed family history and clinical data of the family members were collected and recorded. Whole exome sequencing (WES) was applied in the proband to screen potential genetic variants, and then Sanger sequencing was used to verify the variant within the family. Two hundred unrelated ethnically matched normal individuals (male/female: 100/100, age 37.5 ± 5.5 years) without renal disorder were recruited as controls. Results: Three patients (I:1, II:1 and II:2) presented microscopic hematuria and proteinuria, and the patient I:1 developed uremia and end stage renal disease (ESRD) by age 55 and showed sensorineural hearing loss. Patient II:2 developed mild left ear hearing loss. Cataracts were present in patients I:1 and II:1. A COL4A5 gene missense variant, c.2156G>A (p.G719E), located in the Gly-X-Y repeats of exon 28, was identified to co-segregate with the renal disorder in this family. The variant was absent in 200 ethnically matched controls. Conclusion: By conducting WES and Sanger sequencing, a COL4A5 missense variant, c.2156G>A (p.G719E), was identified to co-segregate with the renal disorder, and it is possible that this variant is the genetic cause of the disorder in this family. Our study may extend the mutation spectrum of XLAS and may be useful for genetic counseling of this family. Further functional studies associated with genetic deficiency are warranted in the following research.

Non-syndromic hearing loss: clinical and diagnostic challenges

2020 ◽  
Vol 32 (2) ◽  
pp. 117-129
Author(s):  
Barbara Vona ◽  
Julia Doll ◽  
Michaela A. H. Hofrichter ◽  
Thomas Haaf
Keyword(s):  
Hearing Loss ◽  
Diagnostic Yield ◽  
Molecular Genetic ◽  
Diagnostic Testing ◽  
Genetic Diagnosis ◽  
Treatment Modalities ◽  
Hereditary Hearing Loss ◽  
Planning Decisions ◽  
Preclinical Trials ◽  
Syndromic Hearing Loss

Abstract Hereditary hearing loss is clinically and genetically heterogeneous. There are presently over 120 genes that have been associated with non-syndromic hearing loss and many more that are associated with syndromic forms. Despite an increasing number of genes that have been implemented into routine molecular genetic diagnostic testing, the diagnostic yield from European patient cohorts with hereditary hearing loss remains around the 50 % mark. This attests to the many gaps of knowledge the field is currently working toward resolving. It can be expected that many more genes await identification. However, it can also be expected, for example, that the mutational signatures of the known genes are still unclear, especially variants in non-coding or regulatory regions influencing gene expression. This review summarizes several challenges in the clinical and diagnostic setting for hereditary hearing loss with emphasis on syndromes that mimic non-syndromic forms of hearing loss in young children and other factors that heavily influence diagnostic rates. A molecular genetic diagnosis for patients with hearing loss opens several additional avenues, such as patient tailored selection of the best currently available treatment modalities, an understanding of the prognosis, and supporting family planning decisions. In the near future, a genetic diagnosis may enable patients to engage in preclinical trials for the development of therapeutics.

scholarly journals A Novel Nonsense Mutation ofPOU4F3Gene Causes Autosomal Dominant Hearing Loss

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Chi Zhang ◽  
Mingming Wang ◽  
Yun Xiao ◽  
Fengguo Zhang ◽  
Yicui Zhou ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Nonsense Mutation ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Stop Codon ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Chinese Family ◽  
Nonsyndromic Hearing Loss ◽  
Truncated Protein

POU4F3gene encodes a transcription factor which plays an essential role in the maturation and maintenance of hair cells in cochlea and vestibular system. Several mutations ofPOU4F3have been reported to cause autosomal dominant nonsyndromic hearing loss in recent years. In this study, we describe a pathogenic nonsense mutation located inPOU4F3in a four-generation Chinese family. Target region capture sequencing was performed to search for the candidate mutations from 81 genes related to nonsyndromic hearing loss in this family. A novel nonsense mutation ofPOU4F3, c.337C>T (p.Gln113⁎), was identified in a Chinese family characterized by late-onset progressive nonsyndromic hearing loss. The novel mutation cosegregated with hearing loss in this family and was absent in 200 ethnicity-matched controls. The mutation led to a stop codon and thus a truncated protein with no functional domains remained. Transient transfection and immunofluorescence assay revealed that the subcellular localization of the truncated protein differed markedly from normal protein, which could be the underlying reason for complete loss of its normal function. Here, we report the first nonsense mutation ofPOU4F3associated with progressive hearing loss and explored the possible underlying mechanism. Routine examination ofPOU4F3is necessary for the genetic diagnosis of hereditary hearing loss in the future.

scholarly journals Unraveling synonymous and deep intronic variants causing aberrant splicing in two genetically undiagnosed epilepsy families

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Qiang Li ◽  
Yiting Wang ◽  
Yijun Pan ◽  
Jia Wang ◽  
Weishi Yu ◽  
...  
Keyword(s):  
Intron Retention ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Aberrant Splicing ◽  
Genetic Test Results ◽  
Functional Consequences ◽  
Intronic Variants

Abstract Background Variants identified through parent–child trio-WES yield up to 28–55% positive diagnostic rate across a variety of Mendelian disorders, there remain numerous patients who do not receive a genetic diagnosis. Studies showed that some aberrant splicing variants, which are either not readily detectable by WES or could be miss-interpreted by regular detecting pipelines, are highly relevant to human diseases. Methods We retrospectively investigated the negative molecular diagnostics through trio-WES for 15 genetically undiagnosed patients whose clinical manifestations were highly suspected to be genetic disorders with well-established genotype–phenotype relationships. We scrutinized the synonymous variants from WES data and Sanger sequenced the suspected intronic region for deep intronic variants. The functional consequences of variants were analyzed by in vitro minigene experiments. Results Here, we report two abnormal splicing events, one of which caused exon truncating due to the activation of cryptic splicing site by a synonymous variant; the other caused partial intron retention due to the generation of splicing sites by a deep intronic variant. Conclusions We suggest that, despite initial negative genetic test results in clinically highly suspected genetic diseases, the combination of predictive bioinformatics and functional analysis should be considered to unveil the genetic etiology of undiagnosed rare diseases.

Sign in / Sign up

Export Citation Format

Share Document