scholarly journals Genetic Characteristics and Phenotype of Korean Patients with Stickler Syndrome: A Korean Multicenter Analysis Report No. 1

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1578
Author(s):  
Soon-Il Choi ◽  
Se-Joon Woo ◽  
Baek-Lok Oh ◽  
Jinu Han ◽  
Hyun-Taek Lim ◽  
...  
Keyword(s):  
Large Scale ◽  
Connective Tissue Disorder ◽  
Stickler Syndrome ◽  
Genetic Characteristics ◽  
Korean Patients ◽  
Missense Variants ◽  
Asian Patients ◽  
Pathogenic Variants ◽  
Splicing Variants ◽  
Multicenter Analysis

Stickler syndrome is an inherited connective tissue disorder of collagen. There are relatively few reports of East Asian patients, and no large-scale studies have been conducted in Korean patients yet. In this study, we retrospectively analyzed the genetic characteristics and clinical features of Korean Stickler syndrome patients. Among 37 genetically confirmed Stickler syndrome patients, 21 types of gene variants were identified, of which 12 were novel variants. A total of 30 people had variants in the COL2A1 gene and 7 had variants in the COL11A1 gene. Among the types of pathogenic variants, missense variants were found in 11, nonsense variants in 8, and splice site variants in 7. Splicing variants were frequently associated with retinal detachment (71%) followed by missense variants. This is the first large-scale study of Koreans with Stickler syndrome, which will expand the spectrum of genetic variations of Stickler syndrome.

Clinical and genetic characteristics of rare pathogenic variants of the CFTR gene in Russian patients with cystic fibrosis

2021 ◽  
Vol 31 (2) ◽  
pp. 148-158
Author(s):  
A. Yu. Voronkova ◽  
Yu. L. Melyanovskaya ◽  
N. V. Petrova ◽  
T. A. Adyan ◽  
E. K. Zhekaite ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Pancreatic Insufficiency ◽  
Protein Energy Malnutrition ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Cftr Gene ◽  
Genetic Characteristics ◽  
Missense Variants ◽  
Pathogenic Variants

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

scholarly journals Biochemical And Genetic Characteristics of Patients With Primary Carnitine Deficiency Identified Through Newborn Screening

2021 ◽  
Author(s):  
Yiming Lin ◽  
Bangbang Lin ◽  
Yanru Chen ◽  
Zhenzhu Zheng ◽  
Qingliu Fu ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Allele Frequency ◽  
Large Scale ◽  
Autosomal Recessive Disorder ◽  
Carnitine Deficiency ◽  
Acid Oxidation ◽  
Genetic Characteristics ◽  
Pathogenic Variants ◽  
Southern Chinese ◽  
Primary Carnitine Deficiency

Abstract Background: Primary carnitine deficiency (PCD) is an autosomal recessive disorder of the carnitine transportation that leads to impaired fatty acid oxidation. Large-scale studies on newborn screening (NBS) for PCD are limited. This study aimed to investigate the biochemical and genetic characteristics of patients with PCD detected by NBS.Results: A total of 548,247 newborns were screened for PCD between January 2014 and June 2021, 1714 newborns had low free carnitine (C0) levels were called back and forty-nine patients were diagnosed with PCD. The latest incidence rate in Quanzhou, China was estimated to be 1 in 11,189 newborns. NBS results showed that all patients had varying degrees of decreased C0 levels, while seven patients exhibited normal C0 levels during recall review. All patients harbored biallelic pathogenic variants in the SLC22A5 gene. Nineteen distinct SLC22A5 variants were detected in the 49 patients, most of the detected variants were clustered in exons 1, 4, and 7. The top eight variants together had an allele frequency of 86.73%. The most common variant was c.760C>T (p.R254*) with an allele frequency of 31.63%, followed by c.51C>G (p.F17L) (17.35%) and c.1400C>G (p.S467C) (16.33%). The C0 level of patients with N/N genotype was significantly lower than that of M/M group. The C0 level of patients with genotypes of R254*/R254* and R254*/F17L were far lower than patients with genotype of R254*/S467C.Conclusions: This study presented more than 500,000 NBS data with the latest incidence of 1:11,189 in Quanzhou area. The SLC22A5 variant spectrum in the selected southern Chinese population was updated. Patients with null variants were associated with low C0 levels. It is necessary to combine genetic testing to improve screening efficiency due to PCD patients may have normal C0 levels during NBS and recall review.

Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications

2019 ◽  
Vol 56 (9) ◽  
pp. 629-638 ◽  
Author(s):  
Lisa Jean Ewans ◽  
Alison Colley ◽  
Carles Gaston-Massuet ◽  
Angelica Gualtieri ◽  
Mark J Cowley ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Clinical Features ◽  
Vascular Complications ◽  
Connective Tissue Disorder ◽  
Stickler Syndrome ◽  
Mineral Density ◽  
Ehlers Danlos Syndrome ◽  
Microarray Expression Data ◽  
Pathogenic Variants ◽  
Microarray Expression

BackgroundPathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease.MethodsReported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features.ResultsKey clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder.ConclusionThese data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.

scholarly journals Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yiming Lin ◽  
Bangbang Lin ◽  
Yanru Chen ◽  
Zhenzhu Zheng ◽  
Qingliu Fu ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Allele Frequency ◽  
Large Scale ◽  
Autosomal Recessive Disorder ◽  
Carnitine Deficiency ◽  
Acid Oxidation ◽  
Genetic Characteristics ◽  
Pathogenic Variants ◽  
Southern Chinese ◽  
Primary Carnitine Deficiency

Abstract Background Primary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation. Large-scale studies on newborn screening (NBS) for PCD are limited. This study aimed to investigate the biochemical and genetic characteristics of patients with PCD detected through NBS. Results A total of 548 247 newborns were screened for PCD between January 2014 and June 2021; 1714 newborns with low free carnitine (C0) levels were called back and 49 patients were diagnosed with PCD. The latest incidence rate in Quanzhou, China, was estimated to be 1 in 11 189 newborns. NBS results showed that the 49 patients had varying degrees of decreased C0 levels, whereas seven patients exhibited normal C0 levels during the recall review. All patients harbored biallelic pathogenic variants of the SLC22A5 gene. Nineteen distinct SLC22A5 variants were detected in these 49 patients, and most of the detected variants were clustered in exons 1, 4, and 7. The top eight variants had an allele frequency of 86.73%. The most common variant was c.760C > T (p.R254*) with an allele frequency of 31.63%, followed by c.51C > G (p.F17L) (17.35%) and c.1400C > G (p.S467C) (16.33%). The C0 level of patients with the N/N genotype was significantly lower than that of the M/M group. The C0 levels of patients with genotypes of R254*/R254* and R254*/F17L were far lower than those of patients with the R254*/S467C genotype. Conclusions This study presented more than 500,000 NBS data with the latest incidence of 1:11 189 in the Quanzhou area. The SLC22A5 variant spectrum in the selected southern Chinese population has been updated. Patients with null variants were associated with low C0 levels. Combining NBS with genetic testing is critical to improve screening efficiency because patients with PCD may have normal C0 levels during NBS and recall review.

scholarly journals Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

2018 ◽  
Vol 103 (3) ◽  
pp. 390-397 ◽  
Author(s):  
Kaoru Fujinami ◽  
Rupert W Strauss ◽  
John (Pei-Wen) Chiang ◽  
Isabelle S Audo ◽  
Paul S Bernstein ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Stargardt Disease ◽  
Genetic Characteristics ◽  
Mild Phenotype ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
Novel Variants ◽  
The Usa ◽  
Subsequent Comparison

Background/aimsTo describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.Methods345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.Results211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.ConclusionsThere is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

scholarly journals Clinical and genetic spectra in patients with dystrophinopathy in Korea: A single-center study

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255011
Author(s):  
UnKyu Yun ◽  
Seung-Ah Lee ◽  
Won Ah Choi ◽  
Seong-Woong Kang ◽  
Go Hun Seo ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Large Scale ◽  
Becker Muscular Dystrophy ◽  
Intermediate Phenotype ◽  
Genetic Characteristics ◽  
Reading Frame ◽  
Pathogenic Variants ◽  
Single Center Study ◽  
Exonic Deletion

Dystrophinopathy is a group of inherited phenotypes arising from pathogenic variants in DMD. We evaluated the clinical and genetic characteristics of Korean patients with genetically confirmed dystrophinopathy. We retrospectively reviewed medical records (January 2004-September 2020) from the myopathy database maintained at the study hospital and found 227 patients from 218 unrelated families with dystrophinopathy. Clinical phenotypes included 120 (53%) Duchenne muscular dystrophy (DMD) cases, 20 (9%) intermediate phenotype muscular dystrophy (IMD) cases, 65 (29%) Becker muscular dystrophy (BMD) cases, 18 (8%) undetermined phenotypes, and 4 (2%) symptomatic carriers. The median ages at symptom onset and diagnosis were 5.0 years (interquartile range [IQR]: 3.8–8.0) and 12.0 years (IQR: 7.0–21.0), respectively. Total manual muscle test (MMT) scores decreased annually in patients with DMD, IMD, and BMD. Overall, when age increased by 1 year, total MMT scores decreased on average by -1.978, -1.681, and -1.303 in patients with DMD (p<0.001), IMD (p<0.001), and BMD (p<0.001), respectively. Exonic deletion and duplication were reported in 147 (67%) and 31 (14%) of the 218 unrelated probands, respectively. A total of 37 different small sequence variants were found in 40 (18%) of the 218 probands. The reading frame rule was applicable to 142 (94%) of the 151 probands. The present results highlight the long-term natural history and genetic spectrum of dystrophinopathy in a large-scale Korean cohort.

scholarly journals Identification of three novel homozygous variants in COL9A3 causing autosomal-recessive Stickler Syndrome

2021 ◽  
Author(s):  
Aboulfazl Rad ◽  
Maryam Najafi ◽  
Fatemeh Suri ◽  
Soheila Abedini ◽  
Stephen Loum ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Molecular Genetics ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Connective Tissue Disorder ◽  
Stickler Syndrome ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Autosomal Dominant Fashion

Abstract Background: Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. Results: Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype-phenotype associations from the literature. Conclusion: Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

scholarly journals Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

2021 ◽  
Author(s):  
Paolo Zanoni ◽  
Katharina Steindl ◽  
Deepanwita Sengupta ◽  
Pascal Joset ◽  
Angela Bahr ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Mild Phenotype ◽  
Psychological Issues ◽  
Missense Variants ◽  
Mild Developmental Delay ◽  
Pathogenic Variants ◽  
In Silico Modeling ◽  
And Function ◽  
Methylation Activity

Abstract Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

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