scholarly journals Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families

2019 ◽  
Vol 28 (2) ◽  
pp. 244-252 ◽  
Author(s):  
Yanqin Zhang ◽  
Jie Ding ◽  
Suxia Wang ◽  
Hongwen Zhang ◽  
Xuhui Zhong ◽  
...  
Keyword(s):  
Alport Syndrome ◽  
Urine Analysis ◽  
Family Members ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
The Other ◽  
Normal Result ◽  
Chinese Families ◽  
Col4a5 Gene ◽  
Pathogenic Variants

Abstract X-linked Alport syndrome (XLAS) is an inherited renal disease caused by mutations in COL4A5 gene. The c.2858G>T(p.(G953V)) in COL4A5 gene (rs78972735) has been considered pathogenic previously. However, there are conflicting interpretations of its pathogenicity recently. Here we presented 19 Chinese families, out of which 36 individuals (18 probands and 18 family members) carried the c.2858G>T(p.(G953V)) in COL4A5 gene. The clinical manifestations and genetic findings of them were analyzed. We found there were no clinical features of Alport syndrome not only in six probands with c.2858G>T(p.(G953V)) in COL4A5 plus pathogenic variants in other genes (e.g., WT1, ADCK4, NPHP1, TRPC6, COL4A4, and PAX2) but also in another six probands with only the c.2858G>T(p.(G953V)) variant. The other six probands with a combination of c.2858G>T(p.(G953V)) and another pathogenic variant in COL4A5 had XLAS. Eleven family members (11/18, nine females and two males) who had only the c.2858G>T(p.(G953V)) variant were asymptomatic. These two males (at age of 42 and 35 years) had normal result of urine analysis and no more clinical traits of Alport syndrome. We conclude c.2858G>T(p.(G953V)) in COL4A5 gene is not a pathogenic variant for XLAS. Individuals should not be diagnosed as XLAS only based on the detection of c.2858G>T(p.(G953V)) in COL4A5 gene.

scholarly journals A distinct APC pathogenic germline variant identified in a southern Thai family with familial adenomatous polyposis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Worrawit Wanitsuwan ◽  
Sukanya Vijasika ◽  
Pichai Jirarattanasopa ◽  
Sukanya Horpaopan
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Donor Site ◽  
Family Members ◽  
Colonic Polyps ◽  
Predictive Testing ◽  
Pathogenic Variant ◽  
Splice Donor Site ◽  
Adenomatous Polyposis ◽  
Transcription Analysis ◽  
Pathogenic Variants

Abstract Background Familial adenomatous polyposis (FAP) is caused by pathogenic germline variants in the APC gene. To date, multiple pathogenic variants in coding regions, splice sites, and deep intronic regions have been revealed. However, there are still pathogenic variants that remain unidentified. Methods Twenty-nine primer pairs flanking exons 2–16 (i.e., coding exons 1–15) of APC and their exon–intron junctions were used for germline pathogenic variant screening in Southern Thai patients with familial adenomatous polyposis (FAP). Transcription analysis was performed to confirm the pathogenicity of a splice site deletion of intron 10. Family members were interviewed for clinical histories. Blood samples were collected from 18 family members for a segregation study. Subsequently, clinical data of affected members were collected from the hospital databases. Results We found a distinct heterozygous 16-bp deletion at the splice donor site of intron 10 leading to a skipping of exon 10 which was confirmed by transcript analysis (APC: c 1312 + 4_1312 + 19del, r.934_1312del). Predictive testing for the pathogenic APC variant in 18 of the proband’s family members (ten healthy and eight affected) from three generations showed the same heterozygous germline pathogenic variant in eight affected adult members (15–62 years old) and two children (7 and 10 years old). Seven of the ten carriers of the disease-causing variant had undergone colonoscopy, and colonic polyps were found in all cases, which confirmed the segregation of the inherited pathogenic variant. The phenotypic spectrum was found to vary within the family; and some affected family members exhibited extracolonic manifestations. Conclusions To our knowledge, the pathogenic APC variant, c.1312 + 4_1312 + 19del, r.934_1312del, has not previously been reported. This study is one of the few reports describing the phenotypic consequences of a pathogenic APC variant in a high number of affected family members.

scholarly journals Generalized Arterial Calcification of Infancy Type 1 (GACI1): Identification of a Novel Pathogenic Variant (c.1715T>C (p.Leu572Ser))

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1034
Author(s):  
Gaetano Pietro Bulfamante ◽  
Laura Carpenito ◽  
Emma Bragantini ◽  
Silvia Graziani ◽  
Maria Bellizzi ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Arterial Calcification ◽  
Medium Size ◽  
Internal Elastic Lamina ◽  
Pathogenic Variants ◽  
Abcc6 Gene ◽  
Enpp1 Gene

Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient’s ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother’s ENPP1 gene, and a sequence analysis of the father’s ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease.

scholarly journals CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2

2021 ◽  
Vol 22 (22) ◽  
pp. 12423
Author(s):  
Sara Morais ◽  
Mónica Pereira ◽  
Catarina Lau ◽  
Ana Gonçalves ◽  
Catarina Monteiro ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Nucleotide Exchange ◽  
Pathogenic Variants ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Heterozygous Carriers

RASGRP2 encodes the calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) identified as a Rap1-activating molecule. Pathogenic variants previously identified in RASGRP2 allowed the characterization of CalDAG-GEFI deficiency as a non-syndromic, autosomal recessive platelet function disease. We report on the clinical manifestations and laboratory features of a Portuguese family with a likely pathogenic variant in RASGRP2 (c.999G>C leading to a p.Lys333Asn change in the CDC25 catalytic domain of CalDAG-GEFI) and discuss the contribution of this variant to the disease manifestations. Based on the study of this family with one homozygous patient and five heterozygous carriers and on a critical analysis of the literature, we challenge previous knowledge that CalDAG-GEFI deficiency only manifests in homozygous patients. Our data suggest that at least for the RASGRP2 variant reported herein, there is a phenotypic expression, albeit milder, in heterozygous carriers.

scholarly journals Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

2019 ◽  
Vol 12 (6) ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby ◽  
Dongchuan Guo ◽  
Wei Zhou ◽  
Maoxuan Lin ◽  
...  
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Age Of Onset ◽  
Family Members ◽  
Aortic Disease ◽  
Pathogenic Variant ◽  
Carrier Status ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
History Of

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6–19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4–22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4–22.3, siblings: OR, 5.1; 95% CI, 1.1–23.9, children: OR, 6.0; 95% CI, 1.4–26.7). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

Comparative Functional Analysis in vitro of 2 COL4A5 Splicing Mutations at the Same Site in 2 Unrelated Alport Syndrome Chinese Families

2020 ◽  
Vol 160 (5) ◽  
pp. 238-244
Author(s):  
Xing Lv ◽  
Wei-Qing Wu ◽  
Jia-Xun Zhang ◽  
Liu-Fei Miao ◽  
Bai-Zeng Yu ◽  
...  
Keyword(s):  
Splice Site ◽  
Alport Syndrome ◽  
Gene Mutations ◽  
Nucleotide Substitutions ◽  
Fragment Analysis ◽  
Chinese Families ◽  
Gene Splicing ◽  
Col4a5 Gene ◽  
Splicing Mutations

X-linked Alport syndrome (XLAS) is a common hereditary nephropathy caused by COL4A5 gene mutations. To date, many splice site mutations have been described but few have been functionally analyzed to verify the exact splicing effects that contribute to disease pathogenesis. Here, we accidentally discovered 2 COL4A5 gene splicing mutations affecting the same residue (c.2917+1G>A and c.2917+1G>C) in 2 unrelated Chinese families. In vitro minigene assays showed that the 2 mutations produced 3 transcripts in H293T cells: one with a 96-bp deletion in exon 33, one with exon 33 skipping, and one with exon 33-34 skipping. However, fragment analysis results showed that the main splicing effects of the 2 mutations were different, the c.2917+1G>A mutation mainly activated a cryptic donor splice site in exon 33 and resulted in the deletion of 96 bp in exon 33, while the c.2917+1G>C mutation mainly caused exon 33 skipping. Our findings indicate that different nucleotide substitutions at the same residue can cause different splicing effects, which may contribute to the variable phenotype of Alport syndrome.

scholarly journals SAT-080 SLC29A3 Pathogenic Variant as a Causal for Dysosteosclerosis, a Poor Osteoclast Form of Osteopetrosis

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Cristian Seiltgens ◽  
Frank Rauch ◽  
Ghalib Bardai
Keyword(s):  
Bone Biopsy ◽  
Osteoclast Differentiation ◽  
Pathogenic Variant ◽  
The Other ◽  
Nucleoside Transporter ◽  
Mineral Density ◽  
Bone Marrow Biopsies ◽  
Femur Fractures ◽  
Pathogenic Variants ◽  
The Individual

Abstract Background: Dysosteosclerosis (DSS) is a rare autosomal recessive form of osteopetrosis characterized by metaphyseal osteosclerosis and platyspondyly. At the histopathological level, a paucity of osteoclasts has been described when the disease presents genetic heterogeneity. SLC29A3 encodes a nucleoside transporter, that colocalizes intracellularly on the lysosomal membrane, is essential for lysosomal function and which is expressed in osteoclasts. Clinical case: We present a female patient from a nonconsanguineous camerunense family with DSS. Her first fracture at the age of 1 year occurred in the proximal right humerus following a very mild trauma. Subsequently she was referred to our clinic at the age of 1.8 months. At the last evaluation in our clinic at the age of 5.6 years she had suffered 5 femur fractures, 2 humerus fractures and a tibia/fibula fracture. XRays shown cortical thickening and widening of the diaphysis of the long bones, cranial base sclerosis, broad ribs with sclerosis and platyspondyly. Bone marrow biopsies and bone biopsy were not performed. The subject did not have any neurological symptoms, dental anomalies or present any dermatological issues. Dual-energy X-ray absorptiometry of the individual showed a lumbar spine BMD Z-score of +8 at 20 months of age, +7.1 at 3 years 5 months, +6.4 at 4 years 6 months and +5.1 at 5 years 6 months of age. TRACP 5 B 4.7 U/L is low in concordance with an osteoclast poor osteopetrosis, and the RANKL&gt;&gt;2.1 ipMol/L is high. On the other hand, CTX 1.298 ng/mL is normal. We identified and confirmed the homozygous pathogenic variant p.Arg386Gln in SLC29A3 using whole exome sequencing and sanger capillary electrophoresis.Conclusion: In summary, we show that a homozygous change in exon 6 of SCL29A3 (NM_00074; c.1157G&gt;A; pArg386Gln) results in a phenotype of Dysosteosclerosis, adding a case to the small group of patients were pathogenic variants in this gene have been described causing sclerosing bone dysplasias with hallmarks of dysosteosclerosis. Interestingly, the other DSS cases and H syndrome cases confirms the clinical heterogeneity of disorders caused by mutations in SLC29A3 and the lack of a clear genotype-phenotype correlation. Phenotypically is also interesting to show that in our patient the bone mineral density has been decreasing over the time, with the concording increasing of TRAB5b. More mutations and functional investigations are needed to get a clearer picture for SCLC29A3 and how is involve in the process of osteoclast differentiation and activity.

scholarly journals Novel Mutations of COL4A5 Identified in Chinese Families with X-Linked Alport Syndrome and Literature Review

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Wen-yu Gong ◽  
Fan-na Liu ◽  
Liang-hong Yin ◽  
Jun Zhang
Keyword(s):  
Literature Review ◽  
Alport Syndrome ◽  
Elevated Serum ◽  
Genetic Diagnosis ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Renal Disorder ◽  
Chinese Families ◽  
Col4a5 Gene ◽  
Male Patients

Alport syndrome (AS) is an inherited kidney disease caused by defects in type IV collagen, which is characterized by hematuria, progressive nephritis or end-stage renal disease (ESRD), hearing loss, and occasionally ocular lesions. Approximately 80% of AS cases are caused by X-linked mutations in the COL4A5 gene. This study explored novel deletion and missense mutations in COL4A5 responsible for renal disorder in two Han Chinese families. In pedigree 1, the five male patients all had ESRD at a young age, while the affected female members only presented with microscopic hematuria. Whole exome sequencing and Sanger sequencing identified a novel frameshift deletion mutation (c.422_428del, p.Leu142Valfs ∗ 11) in exon 7 of COL4A5. In pedigree 2, the 16-year-old male proband had elevated serum creatinine (309 μmol/L) without extrarenal manifestations, while his mother only manifested with hematuria. A missense mutation (c.476G>T, p.Gly159Val) was found in exon 9 of the COL4A5 gene. Neither of these mutations was present in the Exome Variant Server of the NHLBI-ESP database, nor was it found in the ExAC or 1000 Genomes databases. Through the literature review, it was found that male Chinese patients with X-linked AS carried COL4A5 deletion or missense mutations had a more severe phenotype than female patients, particularly in proteinuria and impaired renal function. Compared to male patients with missense mutations, patients in whom deletion mutations were found were more likely to progress to ESRD (15.4% vs. 36.0%, P = 0.041 ). This study identified two novel COL4A5 mutations in Chinese families with X-linked AS, expanded the mutational spectrum of the COL4A5 gene, and presented findings that are significant for the screening and genetic diagnosis of AS.

scholarly journals Phenotypic variability and genetic characteristics of PRRT2-associated paroxysmal movement disorders in 13 Chinese families

2021 ◽  
Author(s):  
Lulu Wu ◽  
Xinyu Yang ◽  
Xiaocui Wang ◽  
Shuang Yu ◽  
Bin Yang
Keyword(s):  
Movement Disorders ◽  
Novel Mutation ◽  
Phenotypic Variability ◽  
Infantile Spasm ◽  
Family Members ◽  
Clinical Findings ◽  
Genetic Characteristics ◽  
Chinese Families ◽  
Pathogenic Variants ◽  
Infantile Epilepsy

Abstract PRRT2-associated paroxysmal movement disorders (PRRT2-PxMDs) include paroxysmal kinesigenic dyskinesias (PKD), benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), episodic ataxia (EA), paroxysmal nonkinesiasgenic dyskinesias (PNKD), and, in addition, other childhood-onset movement disorders and different types of seizures may be caused by PRRT2 mutations, suggesting that the understanding of the spectrum of PRRT2-PxMDs is still evolving. We collected and analyzed retrospectively the clinical of children diagnosed with paroxysmal movement disorders by the Department of Neurology of Anhui Provincial Children's Hospital from January 2015 to June 2020. The genetic tests were performed in the probands and their family members. Thirteen children and their family members, 30 in total, were tested. Twenty six patients and 4 (13.34%) carriers from 13 families were identified, 14 (46.67%) were diagnosed with BIE, 7 (23.33%) with PKD, 2 (6.67%) with ICCA, 1 (3.33%) with epilepsy (focal), 1 (3.33%) with infantile spasm (IS), and 1 (3.33%)was diagnosed with PKD and PNKD, Eight different variants were identified in 13 families, and NM_145239.2:c.640-641insC was found in 4 families while recurrent mutation c.649dupC was not found. Three novel mutation, c.884G > C, c.865G > C, and c.-65-1G > C were identified in this study. This study confirmed that there is no clear genotype-phenotype correlation in patients with PRRT2-PxMDs, in addition, the clinical findings show variable phenotype within families, including the families affected due to the newly identified pathogenic variants in this study.

MULTIPLE ENDOCRINE NEOPLASIA IN PRACTICE OF PRIMARY CARE AND FAMILY PHYISICIANS

2020 ◽  
pp. 11-15
Author(s):  
V. I Pozhar ◽  
O. V. Doroshenko ◽  
M. I. Shevchuk
Keyword(s):  
Family History ◽  
Genetic Analysis ◽  
Multiple Endocrine Neoplasia ◽  
Ganglion Cells ◽  
Family Members ◽  
Clinical Manifestations ◽  
Neurofibromatosis Type ◽  
Endocrine Tumors ◽  
Endocrine Neoplasia ◽  
Cutaneous Lichen Amyloidosis

Multiple endocrine neoplasia is characterized with a predisposition to tumors involving two or more endocrine glands. The four main forms of the disease are inherited as an autosomal dominant syndrome or may occur sporadically. In addition to these four forms, six other syndromes are associated with the presence of multiple endocrine and other neoplasms of the organs: hyperparathyroidism − jaw tumors, Carney complex, von Hippel−Lindau disease, neurofibromatosis type 1, Cowden syndrome and McCune − Albright syndrome. The diagnosis of multiple endocrine neoplasia syndrome can be established in humans by one of the three available criteria: clinical features, family history, genetic analysis. Mutation analysis during these syndromes is useful in clinical practice to confirm the clinical diagnosis; identifying family members who tolerate the mutation and need to be screened, and identifying family members who do not tolerate the mutation. Syndrome of multiple endocrine neoplasia (Wermer syndrome) is characterized by the presence of a triad of tumors, including tumors of the parathyroid glands, pheochromocytoma and tumors of the parathyroid gland. It occurs less frequently in combination with Hirschsprung's disease, caused by the absence of vegetative ganglion cells in the intestine terminal parts, that leads to colonic enlargement, severe constipation and obstruction. This syndrome may be associated with cutaneous lichen amyloidosis, the clinical manifestations of which are pruritus and lichenoid lesions, usually located in the upper back. A clinical case of MEN2 syndrome in a 52−year−old patient is presented. It is noted that for such patients, in addition to timely syndromic rather than component diagnosis of this endocrine multipathology, the spread of neoplastic process in medullary thyroid cancer to its capsule and surrounding tissues, as well as the presence of metastases in peripheral lymph nodes are important. As a rule, such patients cannot be timely cured. Key words: multiple endocrine neoplasia, endocrine tumors, genetic analysis, family history.

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.

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