A DNAH17 missense variant causes flagella destabilization and asthenozoospermia

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.

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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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Turkish cases of Mabry Syndrome with a novel homozygous mutation in PGAP2 gene

10.21203/rs.3.rs-772787/v1 ◽

2021 ◽

Author(s):

Ayşe Kartal ◽

Sandeep Jaiswar

Keyword(s):

Alkaline Phosphatase ◽

Mental Retardation ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Disorder ◽

Missense Variant ◽

Homozygous Mutation ◽

Elevated Alkaline Phosphatase ◽

Dysmorphic Features ◽

Whole Exome

Abstract Hyperphosphatasia with mental retardation syndrome is a genetic disorder. We report two siblings aged three years and fourteen years who were investigated for global development delays, seizures and dysmorphic features. A novel missense variant, c.1003G>A (p. Ala335 Thr chr11.3,846,572 NM_001256236.1), in PGAP2 gene was identified using whole-exome sequencing. We highlight the significance of elevated alkaline phosphatase in patients with certain dysmorphic features, can lead to the diagnosis of hyperphosphatasia with mental retardation syndrome using exome sequencing.

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Case Report: Investigation and molecular genetic diagnosis of familial hypomagnesaemia: a case report

F1000Research ◽

10.12688/f1000research.19006.1 ◽

2019 ◽

Vol 8 ◽

pp. 666

Author(s):

Jamie Willows ◽

Maryam Al Badi ◽

Chloe Richardson ◽

Noel Edwards ◽

Sarah Rice ◽

...

Keyword(s):

Case Report ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Missense Variant ◽

Consanguineous Family ◽

Affected Child ◽

Whole Exome ◽

The Family ◽

Domain Interactions ◽

Molecular Genetic Diagnosis

Genetic mutations causing familial hypomagnesaemia syndromes are well-recognised. Affected patients can present with severe symptoms of hypomagnesaemia, such as seizures or cardiac arrhythmia. We report an affected child, from a consanguineous family, who presented in the first weeks of life with seizures secondary to hypomagnesaemia, without other associated clinical features. We performed whole exome sequencing in the affected child and segregation analysis within the family, which revealed a novel homozygous missense mutation in TRPM6, which was confirmed as a heterozygous allele in both parents and two younger siblings who had transient hypomagnesaemia. Using in silico modelling, we provide evidence that the missense variant p.(K1098E) in TRPM6 is pathogenic, as it disrupts stabilising TRP domain interactions. Management of familial hypomagnesaemia relies on prompt recognition, early magnesium replacement and lifelong monitoring.

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Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

Molecular Case Studies ◽

10.1101/mcs.a006130 ◽

2021 ◽

pp. mcs.a006130

Author(s):

Ryan J Patrick ◽

Jill M Weimer ◽

Laura Davis-Keppen ◽

Megan L Landsverk

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Missense Variant ◽

Facial Features ◽

Loss Of Function ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

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Biallelic Mutations in WDR12 is Associated With Male Infertility With Tapered-Head Sperm

10.21203/rs.3.rs-817537/v1 ◽

2021 ◽

Author(s):

juan hua ◽

Lan Guo ◽

Yao Yao ◽

Yangyang Wan ◽

Wen Hu ◽

...

Keyword(s):

Male Infertility ◽

Molecular Mechanisms ◽

Missense Variant ◽

Bioinformatic Analysis ◽

Chinese Family ◽

Intense Staining ◽

Whole Exome ◽

Repeat Domain ◽

Biallelic Mutations ◽

Pachytene Spermatocytes

Abstract Teratozoospermia is a rare disease associated with male infertility. Unfortunately, approximately 30% of the genetic causes associated with teratozoospermia remain unknown. Several recurrent genetic mutations have been reported to be associated with globozoospermia, macrozoospermia and acephalic spermatozoa, whereas the genetic basis of tapered-head sperm is relatively less well-understood. In this study, whole-exome sequencing (WES) identified a homozygous WD repeat domain 12 (WDR12) (p.Ser162Ala/c.484T>G) variant in an infertile patient with tapered-head sperm from a consanguineous Chinese family. Bioinformatic analysis predicted this mutation to be a pathogenic variant. To further verify the effect of this variant, we analyzed WDR12 protein expression in the patient’s spermatozoa by western blot and found WDR12 to be significantly down-regulated. Also, we found that WDR12 expression is increased in pachytene spermatocytes, and intense staining was visible throughout the round spermatids in mouse testis. Based on our results, we concluded that a rare biallelic pathogenic missense variant (p.Ser162Ala/c.484T>G) in the WDR12 gene causes teratozoospermia. These results will provide novel insights into understanding the molecular mechanisms of male infertility and will help clinicians provide accurate diagnoses.

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

10.21203/rs.3.rs-127028/v1 ◽

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.

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A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family

Audiology and Neurotology ◽

10.1159/000502251 ◽

2019 ◽

Vol 24 (5) ◽

pp. 258-263 ◽

Cited By ~ 2

Author(s):

Mahbobeh Koohiyan ◽

Mohammad Reza Noori-Daloii ◽

Morteza Hashemzadeh-Chaleshtori ◽

Mansoor Salehi ◽

Hamidreza Abtahi ◽

...

Keyword(s):

Hearing Loss ◽

Missense Variant ◽

Pedigree Analysis ◽

Gjb2 Gene ◽

Genetic Linkage Analysis ◽

Complex Process ◽

Whole Exome ◽

The Family ◽

Iranian Family ◽

Molecular Interpretation

Background and Objectives: Hereditary hearing loss (HL) can originate from mutations in one of many genes involved in the complex process of hearing. CABP2 mutations have been reported to cause moderate HL. Here, we report the whole exome sequencing (WES) of a proband presenting with prelingual, severe HL in an Iranian family. Methods: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 2 affected members. After excluding mutations in the GJB2 gene and 7 other most common autosomal recessive nonsyndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis in the family, WES was utilized to find the possible etiology of the disease. Results: WES results showed a novel rare variant (c.311G>A) in the CABP2gene.This missense variant in the exon 4 of the CABP2gene meets the criteria of being pathogenic according to the American College of Medical Genetics and Genomics (ACMG) interpretation guidelines. Conclusions: Up to now, 3 mutations have been reported for the CABP2gene to cause moderate ARNSHL in different populations. Our results show that CABP2variantsalso cause severe ARNSHL, adding CABP2to the growing list of genes that exhibit phenotypic heterogeneity. Expanding our understanding of the mutational spectrum of HL genes is an important step in providing the correct clinical molecular interpretation and diagnosis for patients.

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Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

BioMed Research International ◽

10.1155/2020/4321419 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Xiu-Feng Huang ◽

Li Sun ◽

Chunwu Zhang ◽

Zhenni Zhou ◽

Hui Chen ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Missense Variant ◽

Serum Urate ◽

Functional Domain ◽

Treatment And Prevention ◽

Whole Exome ◽

The Family ◽

General Community

Gout is a common inflammatory arthritis triggered by monosodium urate deposition after longstanding hyperuricemia. In the general community, the disease is largely polygenic in genetic architecture, with many polymorphisms having been identified in gout or urate-associated traits. In a small proportion of cases, rare high penetrant mutations associated with monogenic segregation of the disease in families have been demonstrated to be disease causative. In this study, we recruited a two-generation pedigree with early-onset gout. To elucidate the genetic predisposition, whole-exome sequencing (WES) was performed. After comprehensive variant analyses and cosegregation testing, we identified a missense variant (c.277C>A, p.L93M) in SLC16A9, an extremely rare variant in genetic databases. Moreover, in silico assessments showed strong pathogenicity. This variant cosegregated with the disease phenotype perfectly in the family and is located in a highly conserved functional domain. A few studies supported our results of the association between SLC16A9 and gout and serum urate levels. In conclusion, we provide the first evidence for the association of rare missense in SLC16A9 with early-onset gout. These findings not only expand our current understanding of gout but also may have further implications for the treatment and prevention of gout.

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Turkish cases of Mabry Syndrome with a novel homozygous mutation in PGAP2 gene

10.21203/rs.3.rs-772787/v2 ◽

2021 ◽

Author(s):

Sandeep Jaiswar ◽

Ayşe Kartal

Keyword(s):

Alkaline Phosphatase ◽

Mental Retardation ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Disorder ◽

Missense Variant ◽

Homozygous Mutation ◽

Elevated Alkaline Phosphatase ◽

Dysmorphic Features ◽

Whole Exome

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

Frontiers in Pediatrics ◽

10.3389/fped.2021.774575 ◽

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.

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