Clinical characteristics and genetic analysis of a Chinese pedigree affected with Alström syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic etiology of a Chinese pedigree affected with Alström syndrome.@*METHODS@#A pedigree with 5 members affected with Alström syndrome who had visited the First Affiliated Hospital of Zhengzhou University in February 2021 was selected as the study subject. Clinical data of the pedigree were collected, and peripheral venous blood samples were collected for the extraction of genomic DNA. Genetic testing was carried out for the eldest daughter and third son through whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The eldest daughter (14 years old) and the third son (11 years old) both had congenital nystagmus, amblyopia, growth retardation and type 2 diabetes. WES revealed that both had harbored homozygous c.3538A>T (p.Lys1180*) variant of the ALMS1 gene. Sanger sequencing confirmed that the father, mother, and second daughter were all heterozygous carriers. Based on the Guidelines for Genetic Variation and the Technical Standards for Interpretation and Reporting of Primary Copy Number Variations, the variant was predicted as pathogenic (PVS1+PM2_Supporting+PP4).@*CONCLUSION@#The homozygous c.3538A>T (p.Lys1180*) variant of the ALSM1 gene probably underlay the Alström syndrome in this pedigree, which has provided a reference for the clinical treatment.

Analysis of ALMS1 gene variants in seven patients with Alström syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for 7 patients with Alström syndrome.@*METHODS@#DNA was extracted from peripheral blood samples of the patients and their parents. Whole exome sequencing was carried out for the patients. Suspected variant was verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#Genetic testing revealed 12 variants of the ALMS1 gene among the 7 patients, including 7 nonsense and 5 frameshift variants, which included c.5418delC (p.Tyr1807Thrfs*23), c.10549C>T (p.Gln3517*), c.9145dupC (p.Thr3049Asnfs*12), c.10819C>T (p.Arg3607*), c.5701_5704delGAGA (p.Glu1901Argfs*18), c.9154_9155delCT (p.Cys3053Serfs*9), c.9460delG (p.Val3154*), c.9379C>T (p.Gln3127*), c.12115C>T (p.Gln4039*), c.1468dupA (p.Thr490Asnfs*15), c.10825C>T (p.Arg3609*) and c.3902C>A (p.Ser1301*). Among these, c.9154_ 9155delCT, c.9460delG, c.9379C>T, and c.1468dupA were unreported previously. Based on the standards and guidelines of American College of Medical Genetics and Genomics, the c.9379C>T and c.12115C>T variants of the ALMS1 gene were predicted to be likely pathogenic (PVS1+PM2), whilst the other 10 variants were predicted to be pathogenic (PVS1+ PM2+ PP3+PP4).@*CONCLUSION@#ALMS1 variants probably underlay the Alström syndrome in the 7 patients, and genetic testing can provide a basis for the clinical diagnosis of this syndrome. The discovery of four novel variants has expanded the mutational spectrum of Alström syndrome.

Familial Alström syndrome: a rare cause of bilateral progressive hearing loss / Familial Alström syndrome: a rare cause of bilateral progressive hearing loss

Introdução: A Síndrome de Alstrom é uma doença muito rara, causada pela mutação no gene Obesidade infantil; ALMS1, que apresenta uma degeneração progressiva das funções sensoriais, resultando em de-Diabetes mellitus tipo 2; ficiências visuais e auditivas, além de distúrbios metabólicos como obesidade na infância, hipe-Retinite pigmentosa rinsulinemia e diabetes tipo II. Objetivo: Apresentar o perfil audiométrico de dois irmãos da mesma família afetados pela Síndrome de Alström. Método: Estudo prospectivo, analítico descritivo, os pacientes afetados foram submetidos a um questionário previamente testado, audiometria tonal e vocal seriadas, análise de emissões otoacústicas, e de respostas de potencial evocado auditivo de tronco encefálico, além de análise genético-molecular para comprovação diagnóstica. Resultados: Ambos os pacientes apresentaram perda auditiva bilateral com o início na infância e progressão lenta para perda auditiva neurosensorial severa no primeiro caso e, profunda, no segundo. As emissões otoacústicas estavam ausentes, e o potencial evocado auditivo de tronco encefálico estava normal em ambos os pacientes, bilateralmente. Conclusão: A Síndrome de Alström apresenta início precoce de perda auditiva neurossensorial, antes da adolescência, 10 a 20 anos para desenvolver perda auditiva severa a profunda. A lesão auditiva é essencialmente coclear, de acordo com os resultados dos testes de emissões otoacústicas e de potenciais evocados auditivos de tronco encefálico. .

Introduction: Alström Syndrome is a rare disease caused by mutations in ALMS1 gene. It is characterized by a progressive degeneration of sensory functions, resulting in visual and audiological impairment, as well as metabolic disturbances such as childhood obesity, hyperinsulinemia, and diabetes mellitus type 2. Objective: To report and discuss the genetic and audiological findings in two siblings with Alström syndrome. Methods: This was a prospective, analytical and descriptive study, using questionnaires, serial audiograms, otoacoustic emissions, and auditory brainstem response analysis, as well as molecular genetic analysis. Results: Both patients presented childhood-onset bilateral sensorineural hearing loss, which progressed to moderate impairment in the first case and severe hearing loss in the second. Otoacoustic emissions were absent, and auditory brainstem responses were bilaterally normal in both cases. Conclusion: In the present patients, Alström Syndrome began with a neurosensory hearing loss in early childhood that progressed to a profound loss in ten to twenty years. The auditory lesions were cochlear in origen according to the otoacoustic emissions and auditory brainstem responses. .