Autosomal dominant Shwachman–Diamond syndrome with a novel heterozygous missense variant in the SRP54 gene causing severe phenotypic features

AbstractAt least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localise to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood.In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T>A, p.Ile114Asn.This work demonstrates how in silico modelling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.

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Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia

Blood ◽

10.1182/blood.v96.7.2317 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2317-2322 ◽

Cited By ~ 378

Author(s):

David C. Dale ◽

Richard E. Person ◽

Audrey Anna Bolyard ◽

Andrew G. Aprikyan ◽

Cindy Bos ◽

...

Keyword(s):

Neutrophil Elastase ◽

Rna Splicing ◽

Bacterial Infections ◽

Autosomal Dominant ◽

Mononuclear Cells ◽

Mutational Analysis ◽

Congenital Neutropenia ◽

Gene Encoding ◽

Cyclic Neutropenia ◽

Shwachman Diamond Syndrome

Abstract Congenital neutropenia and cyclic neutropenia are disorders of neutrophil production predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic neutropenia was mapped to chromosome 19p13.3, and this disease is now attributable to mutations of the gene encoding neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital neutropenia is also due to mutations of neutrophil elastase. Patients with congenital neutropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were referred to the Severe Chronic Neutropenia International Registry. Referring physicians provided hematologic and clinical data. Mutational analysis was performed by sequencing polymerase chain reaction (PCR)-amplified genomic DNA for each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mononuclear cells was used to determine if the affected patients expressed both the normal and the abnormal transcript. Twenty-two of 25 patients with congenital neutropenia had 18 different heterozygous mutations. Four of 4 patients with cyclic neutropenia and 0 of 3 patients with Shwachman-Diamond syndrome had mutations. For 5 patients with congenital neutropenia having mutations predicted to alter RNA splicing or transcript structure, reverse transcriptase-PCR showed expression of both normal and abnormal transcripts. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia.

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Unusual Segregation of APP Mutations in Monogenic Alzheimer Disease

Neurodegenerative Diseases ◽

10.1159/000502906 ◽

2019 ◽

Vol 19 (2) ◽

pp. 96-100

Author(s):

Gioia Mastromoro ◽

Stefano Gambardella ◽

Enrica Marchionni ◽

Rosa Campopiano ◽

Alice Traversa ◽

...

Keyword(s):

Alzheimer Disease ◽

Autosomal Dominant ◽

Age Of Onset ◽

Gene Mutations ◽

Missense Variant ◽

The Other ◽

Dominant Trait ◽

Homozygous State ◽

Severe Clinical Picture ◽

App Gene

APP gene mutations causing Alzheimer disease (AD) segregate in an autosomal dominant pattern. We report on a 40-year-old woman with a severe cognitive decline starting at 36 years, while her affected relatives presented symptoms onset in the 6th decade. The proband carried an APP missense variant in homozygous state (NM_000484.4: c.2032G>A; NP_000475.1: p.Asp678Asn; rs63750064) and showed a more severe clinical picture than the other AD relatives, as regards the age of onset and the rate of disease progression. This mutation behaves as a semi-dominant trait. The very rare chance of studying APP mutations in the homozygous state demonstrates they are not always dominant and other segregation models are possible.

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Missense Variant of Endoplasmic Reticulum Region of WFS1 Gene Causes Autosomal Dominant Hearing Loss without Syndromic Phenotype

BioMed Research International ◽

10.1155/2021/6624744 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Jinying Li ◽

Hongen Xu ◽

Jianfeng Sun ◽

Yongan Tian ◽

Danhua Liu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Hearing Loss ◽

Autosomal Dominant ◽

Low Frequency ◽

Missense Variant ◽

Normal Subjects ◽

Pathogenic Variant ◽

Chinese Family ◽

Missense Variants ◽

Wfs1 Gene

Objective. Genetic variants in the WFS1 gene can cause Wolfram syndrome (WS) or autosomal dominant nonsyndromic low-frequency hearing loss (HL). This study is aimed at investigating the molecular basis of HL in an affected Chinese family and the genotype-phenotype correlation of WFS1 variants. Methods. The clinical phenotype of the five-generation Chinese family was characterized using audiological examinations and pedigree analysis. Target exome sequencing of 129 known deafness genes and bioinformatics analysis were performed among six patients and four normal subjects to screen suspected pathogenic variants. We built a complete WFS1 protein model to assess the potential effects of the variant on protein structure. Results. A novel heterozygous pathogenic variant NM_006005.3 c.2020G>T (p.Gly674Trp) was identified in the WFS1 gene, located in the C-terminal domain of the wolframin protein. We further showed that HL-related WFS1 missense variants were mainly concentrated in the endoplasmic reticulum (ER) domain. In contrast, WS-related missense variants are randomly distributed throughout the protein. Conclusions. In this family, we identified a novel variant p.Gly674Trp of WFS1 as the primary pathogenic variant causing the low-frequency sensorineural HL, enriching the mutational spectrum of the WFS1 gene.

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Multicentric Carpotarsal Osteolysis Syndrome in a Mother and Daughter with a MAFB Missense Variant and Natural History of the Disease

Molecular Syndromology ◽

10.1159/000517348 ◽

2021 ◽

pp. 1-6

Author(s):

Kelin Chen ◽

Malú Zamariolli ◽

Maria de Fátima de Faria Soares ◽

Vera Ayres Meloni ◽

Maria Isabel Melaragno

Keyword(s):

Natural History ◽

Autosomal Dominant ◽

Clinical Manifestations ◽

Missense Variant ◽

Heterozygous Variant ◽

Tarsal Bones ◽

Mother And Daughter ◽

Dominant Disease ◽

History Of

Multicentric carpotarsal osteolysis syndrome (MCTO; MIM #166300) is a rare skeletal disorder characterized by osteolysis affecting particularly the carpal, metacarpal, and tarsal bones, although other bones might be involved. MCTO is an autosomal dominant disease caused by heterozygous variants in the <i>MAFB</i> gene, frequently misdiagnosed as juvenile rheumatoid arthritis due to similar clinical manifestations. This study reports the first Brazilian family diagnosed with MCTO with progressive osteolysis of the carpal and tarsal bones, presenting a c.161C>T (p.Ser54Leu) heterozygous variant in the <i>MAFB</i> gene, describing the clinical, radiological, and molecular findings, compared with literature data, and discussing the different clinical and molecular diagnosis, as well as the natural history of the disease. Since MCTO is a disorder with progressive symptoms, an early diagnosis is important to avoid unnecessary investigations and treatments and to provide the proper follow-up.

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Heterozygous Missense Variant in EIF6 gene: a novel form of Shwachman‐Diamond Syndrome?

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.62498 ◽

2021 ◽

Author(s):

Ai Ling Koh ◽

Carine Bonnard ◽

Nur Ain Binte Ali ◽

Bruno Reversade ◽

Saumya Jamuar

Keyword(s):

Missense Variant ◽

Shwachman Diamond Syndrome

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Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant

International Journal of Molecular Sciences ◽

10.3390/ijms22042089 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2089

Author(s):

Ulrich Kellner ◽

Nicole Weisschuh ◽

Silke Weinitz ◽

Ghazaleh Farmand ◽

Sebastian Deutsch ◽

...

Keyword(s):

Autosomal Dominant ◽

Late Onset ◽

Three Dimensional ◽

Missense Variant ◽

Clinical Aspects ◽

Gyrate Atrophy ◽

Three Dimensional Modeling ◽

Long Term Follow Up ◽

The Stability

We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level.

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A novel missense variant in the DIAPH1 gene in a Korean family with autosomal dominant nonsyndromic hearing loss

Genes & Genetic Systems ◽

10.1266/ggs.16-00041 ◽

2016 ◽

Vol 91 (5) ◽

pp. 289-292 ◽

Cited By ~ 4

Author(s):

Tae-Hun Kang ◽

Jeong-In Baek ◽

Borum Sagong ◽

Hong-Joon Park ◽

Chan Ik Park ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Dominant ◽

Missense Variant ◽

Nonsyndromic Hearing Loss ◽

Korean Family ◽

I Gene

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A family with Milroy disease caused by the FLT4/VEGFR3 gene variant c.2774 T > A

BMC Medical Genomics ◽

10.1186/s12920-021-00997-w ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yu Sui ◽

Yongping Lu ◽

Meina Lin ◽

Xiang Ni ◽

Xinren Chen ◽

...

Keyword(s):

Tyrosine Kinase ◽

In Silico ◽

Sanger Sequencing ◽

Autosomal Dominant ◽

Large Family ◽

Missense Variant ◽

Chinese Family ◽

Healthy Controls ◽

Gene Variant ◽

Autosomal Dominant Disorder

Abstract Background Milroy disease (MD) is a rare, autosomal-dominant disorder. Variants in the Fms-related tyrosine kinase 4 (FLT4/VEGFR3) gene cause the symptoms of this disease. In this report, we investigated the variant in a large Chinese family with MD. Methods We conducted Sanger sequencing of exons 17–26 of FLT4/VEGFR3 (NM_182925.4). We assessed its pathogenicity based on the ACMG criteria and predicted it with an in silico program. Results A heterozygous substitution (NM_182925.4 (FLT4/VEGFR3):c.2774 T>A, p. (Val925Glu)) was detected in all patients with MD but not in any healthy controls. The variant was evaluated as pathogenic according to the ACMG criteria and was predicted to be pathogenic using an in silico program. Conclusions In this report, we described a large family with MD caused by a missense variant in FLT4/VEGFR3 (NM_182925.4 (FLT4/VEGFR3_v001):c.2774 T>A, p. (Val925Glu)). There are phenotypic heterogeneities among family members, and further research should be conducted to explore the possible reasons.

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Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia

Blood ◽

10.1182/blood.v96.7.2317.h8002317_2317_2322 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2317-2322 ◽

Cited By ~ 4

Author(s):

David C. Dale ◽

Richard E. Person ◽

Audrey Anna Bolyard ◽

Andrew G. Aprikyan ◽

Cindy Bos ◽

...

Keyword(s):

Neutrophil Elastase ◽

Rna Splicing ◽

Bacterial Infections ◽

Autosomal Dominant ◽

Mononuclear Cells ◽

Mutational Analysis ◽

Congenital Neutropenia ◽

Gene Encoding ◽

Cyclic Neutropenia ◽

Shwachman Diamond Syndrome

Congenital neutropenia and cyclic neutropenia are disorders of neutrophil production predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic neutropenia was mapped to chromosome 19p13.3, and this disease is now attributable to mutations of the gene encoding neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital neutropenia is also due to mutations of neutrophil elastase. Patients with congenital neutropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were referred to the Severe Chronic Neutropenia International Registry. Referring physicians provided hematologic and clinical data. Mutational analysis was performed by sequencing polymerase chain reaction (PCR)-amplified genomic DNA for each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mononuclear cells was used to determine if the affected patients expressed both the normal and the abnormal transcript. Twenty-two of 25 patients with congenital neutropenia had 18 different heterozygous mutations. Four of 4 patients with cyclic neutropenia and 0 of 3 patients with Shwachman-Diamond syndrome had mutations. For 5 patients with congenital neutropenia having mutations predicted to alter RNA splicing or transcript structure, reverse transcriptase-PCR showed expression of both normal and abnormal transcripts. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia.

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