scholarly journals A Novel Homozygous Variant of TMEM231 in a Case With Hypoplasia of the Cerebellar Vermis and Polydactyly

2021 ◽  
Vol 9 ◽  
Author(s):  
Tao Wang ◽  
Yu-Xing Liu ◽  
Fang-Mei Luo ◽  
Yi Dong ◽  
Ya-Li Li ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Genetic Counseling ◽  
Transmembrane Protein ◽  
Missense Variant ◽  
Joubert Syndrome ◽  
Cerebellar Vermis ◽  
Healthy Controls ◽  
Genetic Lesion ◽  
Whole Exome ◽  
Novel Variant

Background: Transmembrane protein 231 (TMEM231) is a component of the B9 complex that participates in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in TMEM231 gene may contribute to the Joubert syndrome (JBTS) or Meckel–Gruber syndrome (MKS). However, reports on JBTS or MKS caused by TMEM231 mutations are comparatively rare.Method: We describe a Chinese fetus with unexplained hypoplasia of the cerebellar vermis and polydactyly, detected by ultrasound imaging. The fetus was primarily diagnosed with JBTS/MKS. The parents of this fetus were non-consanguineous and healthy. Whole-exome sequencing (WES) and bioinformatics strategies were employed to explore the genetic lesion of this family.Results: An unknown missense variant (c.19C>T;p.R7W) of TMEM231 gene was detected. The variant was predicted as pathogenic and was absent in our 200 healthy controls.Conclusion: WES was employed to explore the genetic lesion of a fetus with unexplained hypoplasia of the cerebellar vermis and polydactyly. A novel variant in TMEM231 gene was identified. Our study not only provided data for genetic counseling and prenatal diagnosis to this family but also broadened the spectrum of TMEM231 mutations.

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

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Hao Geng ◽  
Dongdong Tang ◽  
Chuan Xu ◽  
Xiaojin He ◽  
Zhiguo Zhang
Keyword(s):  
Blood Sample ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Sanger Sequencing ◽  
Missense Variant ◽  
Chinese Family ◽  
Peripheral Blood Sample ◽  
Whole Exome ◽  
Novel Variant

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.

A Novel Missense Mutation in NALCN cause CLIFAHDD Syndrome and Prenatal Diagnosis in China

2020 ◽  
Author(s):  
Yuping Li ◽  
Chenglong Zhou ◽  
Yangran Chen ◽  
Haihong Shi ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Bioinformatics Analysis ◽  
Clinical Symptoms ◽  
Missense Variant ◽  
Pathogenic Mutation ◽  
Foot Deformities ◽  
Gene Diagnosis ◽  
Rare Mutations ◽  
Whole Exome ◽  
The Family ◽  
Novel Variant

Abstract Background : CLIFAHDD is caused by mutation in NALCN and characterized by facial malformation, hypotonia, and developmental delay. Recently rare mutations in NALCN associated with of CLIFAHDD syndrome have been reported. Methods : Whole exome sequencing (WES) was applied to a diagnosis suspected CLIFAHDD syndrome proband based on clinical symptoms. Blood samples were taken from the parents of the proband for co-segregation analysis using Sanger sequencing. In addition, prenatal gene diagnosis was performed to the family. Finally bioinformatics analysis was utilized to predict the pathogenesis of novel variant. Result : We reported a 24-hour-old proband with a novel missense variant c.3016G>T (p.Val1006Phe) in NALCN by WES. The proband showed clinical symptoms of head abnormalities, neck shortage, thumbs adduction, positional foot deformities and elbows contracture. Prenatal diagnosis revealed that the proband’s sibling did not carry c.3016G>T. Conclusion : Our findings indicate c.3016G>T is a novel pathogenic mutation, while extending new phenotype CLIFAHDD syndrome and enriching the mutation spectrum of the NALCN gene.

scholarly journals Severe neurodevelopmental disease caused by a homozygous TLK2 variant

2019 ◽  
Vol 28 (3) ◽  
pp. 383-387 ◽  
Author(s):  
Ana Töpf ◽  
Yavuz Oktay ◽  
Sunitha Balaraju ◽  
Elmasnur Yilmaz ◽  
Ece Sonmezler ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Missense Variant ◽  
Cerebellar Vermis ◽  
Language Delay ◽  
Facial Dysmorphism ◽  
Neurodevelopmental Disease ◽  
Whole Exome ◽  
Neurodevelopmental Phenotype

Abstract A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

scholarly journals A DNAH17 missense variant causes flagella destabilization and asthenozoospermia

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Beibei Zhang ◽  
Hui Ma ◽  
Teka Khan ◽  
Ao Ma ◽  
Tao Li ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Male Infertility ◽  
Missense Variant ◽  
Homozygous Mutation ◽  
Common Cause ◽  
Uncharacterized Gene ◽  
Whole Exome ◽  
The Family ◽  
Principal Piece ◽  
Microtubule Doublet

Asthenozoospermia is a common cause of male infertility, but its etiology remains incompletely understood. We recruited three Pakistani infertile brothers, born to first-cousin parents, displaying idiopathic asthenozoospermia but no ciliary-related symptoms. Whole-exome sequencing identified a missense variant (c.G5408A, p.C1803Y) in DNAH17, a functionally uncharacterized gene, recessively cosegregating with asthenozoospermia in the family. DNAH17, specifically expressed in testes, was localized to sperm flagella, and the mutation did not alter its localization. However, spermatozoa of all three patients showed higher frequencies of microtubule doublet(s) 4–7 missing at principal piece and end piece than in controls. Mice carrying a homozygous mutation (Dnah17M/M) equivalent to that in patients recapitulated the defects in patients’ sperm tails. Further examinations revealed that the doublets 4–7 were destabilized largely due to the storage of sperm in epididymis. Altogether, we first report that a homozygous DNAH17 missense variant specifically induces doublets 4–7 destabilization and consequently causes asthenozoospermia, providing a novel marker for genetic counseling and diagnosis of male infertility.

scholarly journals A novel variant of IHH in a Chinese family with brachydactyly type 1

2019 ◽  
Author(s):  
Qi Yang ◽  
Jin Wang ◽  
Xiaoxian Tian ◽  
Fei Chen ◽  
Jing Lan ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Missense Variant ◽  
Chinese Family ◽  
Indian Hedgehog ◽  
Autosomal Dominant Disorder ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variant ◽  
Active Fragment

Abstract Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog ( IHH ). The disorder is mainly characterized by shortening or missing of the middle phalanges. The following study revealed a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene after performing whole-exome sequencing in the proband of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the variants on IHH gene which contribute to the cause of BDA-1.

scholarly journals Identification of a Novel Variant of ARHGAP29 in a Chinese Family with Nonsyndromic Cleft Lip and Palate

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Jian-Xia Tang ◽  
Xiang-Shui Xiao ◽  
Kai Wang ◽  
Jie-Yuan Jin ◽  
Liang-Liang Fan ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variant ◽  
Development Methods

Background. Cleft lip with or without cleft palate (CL/P) is the most common facial birth defect, with a worldwide incidence of 1 in 700-1000 live births. CL/P can be divided into syndromic CL/P (SCL/P) and nonsyndromic CL/P (NSCL/P). Genetic factors are an important component to the etiology of NSCL/P. ARHGAP29, one of the NSCL/P disease-causing genes, mediates the cyclical regulation of small GTP binding proteins such as RhoA and plays an essential role in cellular shape, proliferation, and craniofacial development. Methods. The present study investigated a Chinese family with NSCL/P and explored potential pathogenic variants using whole-exome sequencing (WES). Variants were screened and filtered through bioinformatic analysis and prediction of variant pathogenicity. Cosegregation was subsequently conducted. Results. We identified a novel heterozygous missense variant of ARHGAP29 (c.2615C > T, p.A872V) in a Chinese pedigree with NSCL/P. Conclusion. We detected the disease-causing variant in this NSCL/P family. Our identification expands the genetic spectrum of ARHGAP29 and contributes to novel approaches to the genetic diagnosis and counseling of CL/P families.

scholarly journals A novel variant of IHH in a Chinese family with brachydactyly type 1

2020 ◽  
Author(s):  
Qi Yang ◽  
Jin Wang ◽  
Xiaoxian Tian ◽  
Fei Chen ◽  
Jing Lan ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Missense Variant ◽  
Chinese Family ◽  
Indian Hedgehog ◽  
Autosomal Dominant Disorder ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variant ◽  
Active Fragment

Abstract Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog ( IHH ). The disorder is mainly characterized by shortening or missing of the middle phalanges. The following study revealed a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene after performing whole-exome sequencing in the proband of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the variants on IHH gene which contribute to the cause of BDA-1.

scholarly journals A Novel Missense Mutation in NALCN Cause CLIFAHDD Syndrome and Prenatal Diagnosis in China

2021 ◽  
Author(s):  
Yuping Li ◽  
Chenglong Zhou ◽  
Yangran Chen ◽  
Haihong shi ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Clinical Symptoms ◽  
Missense Variant ◽  
Pathogenic Mutation ◽  
Foot Deformities ◽  
Gene Diagnosis ◽  
Rare Mutations ◽  
Whole Exome ◽  
The Family ◽  
Novel Variant

Abstract Background: CLIFAHDD is caused by mutation in NALCN and characterized by facial malformation, hypotonia, and developmental delay. Recently rare mutations in NALCN associated with of CLIFAHDD syndrome have been reported. Methods: Whole exome sequencing (WES) was applied to a diagnosis suspected CLIFAHDD syndrome proband based on clinical symptoms. Blood samples were taken from the parents of the proband for co-segregation analysis using Sanger sequencing. In addition, prenatal gene diagnosis was performed to the family. Finally bioinformatics analysis was utilized to predict the pathogenesis of novel variant. Result: We reported a 24-hour-old proband with a novel missense variant c.3016G>T (p.Val1006Phe) in NALCN by WES. The proband showed clinical symptoms of head abnormalities, neck shortage, thumbs adduction, positional foot deformities and elbows contracture. Prenatal diagnosis revealed that the proband’s sibling did not carry c.3016G>T. Conclusion: Our findings indicate c.3016G>T is a novel pathogenic mutation, while extending new phenotype CLIFAHDD syndrome and enriching the mutation spectrum of the NALCN gene.

scholarly journals A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND1

2021 ◽  
Author(s):  
Kumiko Yanagi ◽  
Noriko Morimoto ◽  
Manami Iso ◽  
Yukimi Abe ◽  
Kohji Okamura ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Morphological Characteristics ◽  
Missense Variant ◽  
Nucleotide Binding ◽  
Sequencing Analysis ◽  
Guanine Nucleotide ◽  
Guanine Nucleotide Binding Protein ◽  
Computer Tomography Scan ◽  
Novel Variant ◽  
Guanine Nucleotide Binding

AbstractAuriculocondylar syndrome (ARCND) is an autosomal monogenic disorder characterised by external ear abnormalities and micrognathia due to hypoplasia of the mandibular rami, condyle and coronoid process. Genetically, three subtypes of ARCND (ARCND1, ARCND2 and ARCND3) have been reported. To date, five pathogenic variants of GNAI3 have been reported in ARCND1 patients. Here, we report a novel variant of GNAI3 (NM_006496:c.807C>A:p.(Asn269Lys)) in a Japanese girl with micrognathia using trio-based whole exome sequencing analysis. The GNAI3 gene encodes a heterotrimeric guanine nucleotide-binding protein. The novel variant locates the guanine nucleotide-binding site, and the substitution was predicted to interfere with guanine nucleotide-binding by in silico structural analysis. Three-dimensional computer tomography scan, or cephalogram, displayed severely hypoplastic mandibular rami and fusion to the medial and lateral pterygoid plates, which have been recognised in other ARCND1 patients, but have not been described in ARCND2 and ARCND3, suggesting that these may be distinguishable features in ARCND1.

scholarly journals Lateral diffusion of wild-type and mutant Ld antigens in L cells.

1984 ◽  
Vol 99 (6) ◽  
pp. 2333-2335 ◽  
Author(s):  
M Edidin ◽  
M Zuniga
Keyword(s):  
Plasma Membrane ◽  
Diffusion Coefficients ◽  
Transmembrane Protein ◽  
Transmembrane Proteins ◽  
Lateral Diffusion ◽  
Cytoplasmic Domain ◽  
Histocompatibility Antigen ◽  
Wild Type ◽  
Major Histocompatibility Antigen ◽  
Cytoplasmic Side

We have compared the lateral diffusion of intact transmembrane proteins, wild-type H-2Ld antigens, with that of mutants truncated in the cytoplasmic domain. Diffusion coefficients and mobile fractions were similar for all molecules examined, from wild-type Ld antigens with 31 residues on the cytoplasmic side of the plasma membrane to mutants with only four residues in the cytoplasmic domain. This result limits ways in which the lateral diffusion of a major histocompatibility antigen, a transmembrane protein, can be constrained by interactions with other molecules.

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