scholarly journals Prevalent ALMS1 Pathogenic Variants in Spanish Alström Patients

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 282
Author(s):  
Brais Bea-Mascato ◽  
Carlos Solarat ◽  
Irene Perea-Romero ◽  
Teresa Jaijo ◽  
Fiona Blanco-Kelly ◽  
...  
Keyword(s):  
High Frequency ◽  
Haplotype Analysis ◽  
Genetic Diagnosis ◽  
Allelic Frequency ◽  
Structural Protein ◽  
Alström Syndrome ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Alstrom Syndrome

Alström syndrome (ALMS) is an ultrarare disease with an estimated prevalence lower than 1 in 1,000,000. It is associated with disease-causing mutations in the Alström syndrome 1 (ALMS1) gene, which codifies for a structural protein of the basal body and centrosomes. The symptomatology involves nystagmus, type 2 diabetes mellitus (T2D), obesity, dilated cardiomyopathy (DCM), neurodegenerative disorders and multiorgan fibrosis. We refined the clinical and genetic diagnosis data of 12 patients from 11 families, all of them from Spain. We also studied the allelic frequency of the different variants present in this cohort and performed a haplotype analysis for the most prevalent allele. The genetic analysis revealed 2 novel homozygous variants located in the exon 8, p.(Glu929Ter) and p.(His1808GlufsTer20) in 2 unrelated patients. These 2 novel variants were classified as pathogenic after an in silico experiment (computer analysis). On the other hand, 2 alleles were detected at a high frequency in our cohort: p.(Tyr1714Ter) (25%) and p.(Ser3872TyrfsTer19) (16.7%). The segregation analysis showed that the pathogenic variant p.(Tyr1714Ter) in 3 families is linked to a rare missense polymorphism, p.(Asn1787Asp). In conclusion, 2 novel pathological mutations have been discovered in homozygosis, as well as a probable founder effect in 3 unrelated families.

scholarly journals High Prevalence Mutations in ALMS1 in Spanish Alström Patients

2020 ◽  
Author(s):  
Brais Bea Mascato ◽  
Carlos López Solarat ◽  
Irene Perea Romeo ◽  
Teresa Jaijo ◽  
Fiona Blanco Kelly ◽  
...  
Keyword(s):  
Haplotype Analysis ◽  
Allelic Frequency ◽  
Structural Protein ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Alström Syndrome ◽  
High Prevalence ◽  
Alstrom Syndrome ◽  
Organ Fibrosis

Abstract Background:Alström syndrome (ALMS) is a rare disease with an estimated prevalence lower than 1 in 1,000,000. It is associated with mutations in the Alström syndrome 1 (ALMS1) gene, which codifies for a structural protein of the basal body and centrosomes. Symptomatology involves nystagmus, type 2 diabetes mellitus (DM2), obesity, dilated cardiomyopathy (DMC), neurodegenerative disorders and multi-organ fibrosis.Methods:We included the clinical data of 13 patients from 12 families, all of them from Spain. We studied the allelic frequency for the different mutations present in this cohort and we perform a haplotype analysis for the most prevalent allele.Results:Two alleles were detected in high frequency: p.(Tyr1714Ter) (0,25) and p.(Ser3872TyrfsTer19) (0,167). The segregation analysis of the mutation p.(Tyr1714Ter) in 3 families shows that it is linked to a rare missense polymorphism. Also, we detect an ancestral haplotype for ALMS1 in three families.Conclusion:Mutation p.(Tyr1714Ter) co-segregates with a rare single nucleotide polymorphism (SNP) that could be arise by a founder effect in the Iberian Peninsula.

scholarly journals Geographical Variation in the profile of RET Variants in Patients with Medullary Thyroid Cancer: A Comprehensive Review

2021 ◽  
Author(s):  
Rui M. B. Maciel ◽  
Ana Luiza Maia
Keyword(s):  
Haplotype Analysis ◽  
Medullary Thyroid Cancer ◽  
Genetic Diagnosis ◽  
Epidemiological Data ◽  
Global Perspective ◽  
Causative Role ◽  
Medullary Thyroid ◽  
Pathogenic Variants

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98%, 50% and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants have been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

scholarly journals A Case Report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Author(s):  
Maria Fedorovna Shurygina ◽  
Maria A. Parker ◽  
Catie Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Light Sensitivity ◽  
Clinical Findings ◽  
Alström Syndrome ◽  
Mild Developmental Delay ◽  
Novel Variants ◽  
Normal Stature ◽  
Alstrom Syndrome

Abstract Background Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with novel biallelic changes in ALMS1. Case presentation Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298fs) and c.10769delC (p.T3590fs) in ALMS1 gene were found. Conclusions Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.

scholarly journals A Case Report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Author(s):  
Maria Fedorovna Shurygina ◽  
Maria A. Parker ◽  
Catie Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Light Sensitivity ◽  
Clinical Findings ◽  
Alström Syndrome ◽  
Mild Developmental Delay ◽  
Novel Variants ◽  
Normal Stature ◽  
Alstrom Syndrome

Abstract Background Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with novel biallelic changes in ALMS1. Case presentation Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298fs) and c.10769delC (p.T3590fs) in ALMS1 gene were found. Conclusions Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.

scholarly journals A Case Report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Author(s):  
Maria Fedorovna Shurygina ◽  
Maria A. Parker ◽  
Catie Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Light Sensitivity ◽  
Clinical Findings ◽  
Alström Syndrome ◽  
Mild Developmental Delay ◽  
Novel Variants ◽  
Normal Stature ◽  
Alstrom Syndrome

Abstract Background Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with novel biallelic changes in ALMS1. Case presentation Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298fs) and c.10769delC (p.T3590fs) in ALMS1 gene were found. Conclusions Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.

scholarly journals A case report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Maria F. Shurygina ◽  
Maria A. Parker ◽  
Catie L. Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Light Sensitivity ◽  
Clinical Findings ◽  
Alström Syndrome ◽  
Mild Developmental Delay ◽  
Novel Variants ◽  
Normal Stature ◽  
Alstrom Syndrome

Abstract Background Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with two novel changes in ALMS1. Case presentation Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298 fs) and c.10769delC (p.T3590 fs) in ALMS1 gene were found. Conclusions Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.

scholarly journals UNUSUAL PRESENTATIONS OF LMNA-ASSOCIATED LIPODYSTROPHY WITH COMPLEX PHENOTYPES AND GENERALIZED FAT LOSS: WHEN THE GENETIC DIAGNOSIS UNCOVERS NOVEL FEATURES

2020 ◽  
Vol 6 (2) ◽  
pp. e79-e85
Author(s):  
Natalia Xavier S. de Andrade ◽  
Suleyman Cem Adiyaman ◽  
Berna Demir Yuksel ◽  
Carla T. Ferrari ◽  
Abdelwahab Jalal Eldin ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Pathogenic Variant ◽  
The Body ◽  
Muscle Disease ◽  
Partial Lipodystrophy ◽  
Fat Loss ◽  
Pathogenic Variants ◽  
Complex Phenotypes ◽  
Familial Partial Lipodystrophy

Objective: Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants. Methods: We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging. Results: We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the LMNA gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous LMNA pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma. Conclusion: Clinicians need to recognize that the presence of an LMNA variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.

scholarly journals Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes

2018 ◽  
Author(s):  
Jessica E. Nesmith ◽  
Timothy L. Hostelley ◽  
Carmen C. Leitch ◽  
Maggie S. Matern ◽  
Saumil Sethna ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Single Gene ◽  
Loss Of Function ◽  
Β Cells ◽  
Zebrafish Model ◽  
Alström Syndrome ◽  
Alstrom Syndrome

SCIENTIFIC ABSTRACTAlström syndrome is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration, and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early onset type 2 diabetes mellitus (T2DM). To investigate mechanisms linking disease phenotypes we generated a loss-of-function deletion of alms1 in the zebrafish using CRISPR/Cas9. We demonstrate conserved phenotypic effects including cardiac defects, retinal degeneration, and metabolic deficits that included propensity for obesity and fatty livers in addition to hyperinsulinemia and glucose response defects. Gene expression changes in β-cells isolated from alms1−/− mutants revealed changes consistent with insulin hyper-secretion and glucose sensing failure, which were also identified in cultured murine β-cells lacking Alms1. These data present a zebrafish model to assess etiology and new secretory pathway defects underlying Alström syndrome-associated metabolic phenotypes. Given the hyperinsulinemia and reduced glucose sensitivity in these animals we also propose the alms1 loss-of-function mutant as a monogenic model for studying T2DM phenotypes.AUTHOR SUMMARYThese data comprise a thorough characterization of a zebrafish model of Alström syndrome, a human obesity syndrome caused by loss-of-function deletions in a single gene, ALMS1. The high rates of obesity and insulin resistance found in these patients suggest this disorder as a single-gene model for Type 2 Diabetes Mellitus (T2DM), a disorder caused by a variety of environmental and genetic factors in the general population. We identify a propensity for obesity, excess lipid storage, loss of β-cells in islets, and hyperinsulinemia in larval and adult stages of zebrafish alms1 mutants. We isolated β-cells from the alms1 mutants and compared the gene expression profiles from RNASeq datasets to identify molecular pathways that may contribute to the loss of β-cells and hyperinsulinemia. The increase in genes implicated in generalized pancreatic secretion, insulin secretion, and glucose transport suggest potential β-cell exhaustion as a source of β-cell loss and excess larval insulin. We propose this mutant as a new genetic tool for understanding the metabolic failures found in Type 2 Diabetes Mellitus.

Sign in / Sign up

Export Citation Format

Share Document