Autosomal Dominant Familial Intestinal Varicosis and Polyposis coli is associated with Pathogenic Variants in NKX2.3

Background Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia. Objectives To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes. Methods We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects. Results Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity. Conclusions Previously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.

Download Full-text

Cantu syndrome and hypopituitarism: implications for endocrine monitoring

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-19-0103 ◽

2019 ◽

Vol 2019 ◽

Author(s):

Nicholas J Theis ◽

Toby Calvert ◽

Peter McIntyre ◽

Stephen P Robertson ◽

Benjamin J Wheeler

Keyword(s):

Anterior Pituitary ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Facial Features ◽

Pituitary Hormone ◽

List Type ◽

Pituitary Dysfunction ◽

Pathogenic Variants ◽

Clinical Surveillance ◽

Learning Points

Summary Cantu syndrome, or hypertrichotic osteochondrodysplasia, is a rare, autosomal dominant genetically heterogeneous disorder. It is characterized by hypertrichosis, cardiac and skeletal anomalies and distinctive coarse facial features. We report a case where slowed growth velocity at 13 years led to identification of multiple pituitary hormone deficiencies. This adds to other reports of pituitary abnormalities in this condition and supports inclusion of endocrine monitoring in the clinical surveillance of patients with Cantu syndrome. Learning points: Cantu syndrome is a rare genetic disorder caused by pathogenic variants in the ABCC9 and KCNJ8 genes, which result in gain of function of the SUR2 or Kir6.1 subunits of widely expressed KATP channels. The main manifestations of the syndrome are varied, but most commonly include hypertrichosis, macrosomia, macrocephaly, coarse ‘acromegaloid’ facies, and a range of cardiac defects. Anterior pituitary dysfunction may be implicated in this disorder, and we propose that routine screening should be included in the clinical and biochemical surveillance of patients with Cantu syndrome.

Download Full-text

A novel CRYBB2 mutation causes autosomal dominant cataract: A report from a Chinese family

European Journal of Ophthalmology ◽

10.1177/1120672120926450 ◽

2020 ◽

pp. 112067212092645

Author(s):

Li Juan Xu ◽

Zhi Gang Lv ◽

Ying Liu ◽

Xiang Xiang Zhang ◽

Yu Xin Cui ◽

...

Keyword(s):

Axial Length ◽

Healthy Subjects ◽

Sanger Sequencing ◽

Autosomal Dominant ◽

Pathogenic Mutation ◽

Chinese Family ◽

Rare Mutation ◽

Pathogenic Variants ◽

Lens Opacities ◽

Generation Sequencing

Purpose This study aimed to examine pathogenic mutation within one Chinese family of five-generations suffering from autosomal dominant cataract. Methods Next-generation sequencing and Sanger sequencing were used to find the pathogenic variants. Results A rare mutation, c.563G > A, in CRYBB2 gene was found in the proband that showed symptom of non-syndromic congenital autosomal dominant cataract. This mutation had been found in all affected individuals and in one healthy infant, but it did not exist between two individuals who did not develop such disease in that family, as well as in 100 healthy subjects who showed no relation with that family. Cataracts in this family varied with different severity of lens opacities and elongation of axial length. Conclusion One missense mutation c.563G > A is reported in the CRYBB2 gene among one Chinese family suffering from early-onset cataract, and associated novel phenotypes are the elongation of axial length and the types of cataract. Our results expand the spectrum of associated phenotypes of CRYBB2 mutation.

Download Full-text

Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature

Journal of Pediatric Genetics ◽

10.1055/s-0039-1698446 ◽

2019 ◽

Vol 09 (02) ◽

pp. 117-120

Author(s):

Pavalan Selvam ◽

Shekhar Singh ◽

Angita Jain ◽

Herjot Atwal ◽

Paldeep S. Atwal

Keyword(s):

Sequence Analysis ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Review Of The Literature ◽

Pathogenic Variants ◽

Phenotypic Spectrum ◽

Whole Exome ◽

The Family ◽

Type Xi Collagen ◽

Exome Sequence

AbstractOtospondylomegaepiphyseal dysplasia (OSMED) is an inherited autosomal dominant and recessive skeletal dysplasia caused by both heterozygous and homozygous pathogenic variants in COL11A2 encoding the α2(XI) collagen chains, a part of type XI collagen. Here, we describe a 2-year-old girl presenting from birth with a phenotype suggestive of OSMED. On whole exome sequence analysis of the family via commercially available methods, we detected two novel heterozygous pathogenic variants in the proband. In addition, we reviewed the phenotype of autosomal recessive OSMED cases with COL11A2 pathogenic variants reported to date and quantitatively highlighted the phenotypic spectrum.

Download Full-text

A Comprehensive Review on Inherited Sensorineural Hearing Loss and Their Syndromes

10.20944/preprints202008.0308.v1 ◽

2020 ◽

Author(s):

Muhammad Noman ◽

Shazia Anwer Bukhari ◽

Muhammad Tahir ◽

Shehbaz Ali

Keyword(s):

Hearing Loss ◽

Hearing Impairment ◽

Autosomal Dominant ◽

Genetic Disorders ◽

World Population ◽

Pathogenic Variants ◽

Pathogenic Genes ◽

Whole Exome ◽

Specific Locus ◽

Population Effects

Hearing impairment is an immensely diagnosed genetic cause, 5% of the total world population effects with different kind of congenital hearing loss (HL). In third-world countries or countries where consanguineous marriages are more common the frequency rate of genetic disorders are at its zenith. Approximately, the incidence of hearing afflictions is ostensibly 7-8:1000 individuals whereas it is estimated that about 466 million peoples suffer with significant HL, and of theses deaf cases 34 million are children’s up to March, 2020. Several genes and colossal numbers of pathogenic variants cause hearing impairment, which aided in next-generation with recessive, dominant or X-linked inheritance traits. This review highlights on syndromic and non-syndromic HL (SHL and NSHL), and categorized as conductive, sensorineural and mixed HL, which having autosomal dominant and recessive, and X-linked or mitochondrial mode of inheritance. Many hundred genes involved in HL are reported, and their mutation spectrum becomes very wide. Mapping of pathogenic genes in consanguinity family is facilitated to understand the disease history. Review presents the bases of HL and also focused on various genetic factors that cause deafness like the basics of genetic inheritance, and classic and well-characterized inherited factors of it. It also overviews the application of linkage analysis, SNPs genotyping and whole exome sequencing methods, in mapping and identification of new locus, causative genes and their variants in families inherited with HL. Conclusively, this review supports researchers in understanding the location of chromosome, the causative genes and specific locus which causing deafness in humans.

Download Full-text

Fontaine Progeroid Syndrome -- A Case Report

10.22541/au.163836794.49669766/v1 ◽

2021 ◽

Author(s):

Sinead Lally ◽

Nicola Walsh ◽

Janna Kenny ◽

Orla Franklin ◽

Melanie Cotter ◽

...

Keyword(s):

Case Report ◽

Autosomal Dominant ◽

Clinical Course ◽

Chromosome 1 ◽

Progeroid Syndrome ◽

Autosomal Dominant Condition ◽

Pathogenic Variants ◽

Dominant Condition ◽

Early Lethality

Fontaine Progeroid Syndrome (FPS) is an autosomal dominant condition caused by pathogenic variants in the SLC25A24 gene located on chromosome 1. Eleven cases have been described in the literature, with early lethality in some. We discuss the clinical course of a patient from birth until his death at 7 months.

Download Full-text

Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer disease brains

10.1101/2021.11.04.21265941 ◽

2021 ◽

Author(s):

Brenna C Novotny ◽

Maria-Victoria Fernandez ◽

Jorge Bahena ◽

John P Budde ◽

Kristy Bergmann ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer Disease ◽

Genetic Risk ◽

Autosomal Dominant ◽

Late Onset ◽

Disease Status ◽

Genetic Risk Factors ◽

Web Browser ◽

Pathogenic Variants ◽

Genetic Groups

The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence to support that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain, including information on treatment targets. In this study, we interrogate the metabolomic and lipidomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ϵ4 and TREM2 risk variant carriers, and non-carrier sporadic AD (sAD). We generated metabolomic and lipidomic data from parietal cortical tissue from 366 participants with AD pathology and 26 cognitively unimpaired controls using the Metabolon global metabolomics platform. We identified 133 metabolites associated with disease status (FDR q-value<0.05). In sAD brains these include tryptophan betaine (b=-0.57) and N-acetylputrescine (b=-0.14). Metabolites associated with sAD and ADAD include ergothioneine (b=-0.21 and -0.26 respectively) and serotonin (b=-0.34 and -0.58, respectively). TREM2 and ADAD showed association with α-tocopherol (b=-0.12 and -0.12) and CDP-ethanolamine (b=-0.13 and -0.10). β-citrylglutamate levels are associated with sAD, ADAD, and TREM2 compared to controls (b=-0.15; -0.22; and -0.29, respectively). Additionally, we identified a signature of 16 metabolites that is significantly altered between genetic groups (sAD vs. control p = 1.05x10-7, ADAD vs. sAD p = 3.21x10-5) and is associated with Braak tau stage and disease duration. These data are available to the scientific community through a public web browser (http://ngi.pub/Metabolomics). Our findings were replicated in an independent cohort of 327 individuals.

Download Full-text

Coinheritance of 2 New Potentially Damaging Heterozygous COL7A1 Variants in a Family With Autosomal Dominant Epidermolysis Bullosa Pruriginosa

Pediatric and Developmental Pathology ◽

10.1177/1093526618761497 ◽

2018 ◽

Vol 21 (6) ◽

pp. 580-584

Author(s):

Gordon I Hale ◽

Marta C Cohen ◽

Oliver W Quarrell ◽

John A McGrath ◽

Andrew G Messenger

Keyword(s):

Epidermolysis Bullosa ◽

Autosomal Dominant ◽

Late Onset ◽

Phenotypic Variability ◽

Incomplete Penetrance ◽

Histopathological Diagnosis ◽

Delayed Presentation ◽

Pathogenic Variants ◽

Type Vii Collagen ◽

Phenotypic And Genotypic Variability

Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of EB which is characterized by intense pruritus with blistering and nodular or lichenoid lesions most prominent on the lower extremities. It is caused by variants in COL7A1 which encodes for type VII collagen. There is wide phenotypic and genotypic variability between affected individuals. We report 2 potentially pathogenic variants in COL7A1 occurring on the same allele in a family with EBP and autosomal dominant inheritance. Late-onset EBP and incomplete penetrance may lead to delayed presentation in affected family members with the same variants. The broad phenotypic variability seen in EBP suggests that further genotypic and environmental factors may influence presentation. Genetic and histopathological diagnosis is essential, given the considerable overlap with clinically similar presentations such as hypertrophic lichen planus.

Download Full-text

Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

Neuropediatrics ◽

10.1055/s-0040-1701671 ◽

2020 ◽

Vol 51 (04) ◽

pp. 245-250

Author(s):

Chloé Angelini ◽

Marie Thibaud ◽

Nathalie Aladjidi ◽

Pierre Bessou ◽

Sébastien Cabasson ◽

...

Keyword(s):

Autosomal Recessive ◽

Autosomal Dominant ◽

De Novo ◽

Cutis Laxa ◽

Variable Degree ◽

Severe Phenotype ◽

Pathogenic Variants ◽

Type Iiia ◽

Recessive Type ◽

Neurological Phenotype

AbstractCutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.

Download Full-text

Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107150 ◽

2020 ◽

pp. jmedgenet-2020-107150

Author(s):

Guillaume Olivier ◽

Marta Corton ◽

Daniela Intartaglia ◽

Sanne K Verbakel ◽

Panagiotis I Sergouniotis ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Exome Sequencing ◽

Autosomal Dominant ◽

Macular Dystrophy ◽

Common Disease ◽

Medaka Fish ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing

BackgroundInherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.MethodsExome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role.ResultsExome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.ConclusionThis study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.

Download Full-text