scholarly journals Identification of Four Novel Variants and Determination of Genotype–Phenotype Correlations for ABCA4 Variants Associated With Inherited Retinal Degenerations

2021 ◽  
Vol 9 ◽  
Author(s):  
Qing Zhu ◽  
Xue Rui ◽  
Ya Li ◽  
Ya You ◽  
Xun-Lun Sheng ◽  
...  
Keyword(s):  
Splice Site Mutation ◽  
Missense Variant ◽  
Cone Dystrophy ◽  
Missense Mutations ◽  
Site Mutation ◽  
Targeted Next Generation Sequencing ◽  
Retinal Degenerations ◽  
Pathogenic Variants ◽  
Physico Chemical ◽  
Type 3

PurposeThe purpose of the study is to describe the genetic and clinical features of 17 patients with ABCA4-related inherited retinal degenerations (IRDs) and define the phenotype–genotype correlations.MethodsIn this multicenter retrospective study, 17 patients from 16 families were enrolled, and ABCA4 gene variants were detected using targeted next-generation sequencing using a custom designed panel for IRDs. Sanger sequencing and co-segregation analysis of the suspected pathogenic variants were performed with the family members. The pathogenicities of variants were evaluated according to the American College of Medical Genetics and Genomics guidelines (ACMG). Protein structure modifications mediated by the variants were studied using bioinformatic analyses.ResultsThe probands were diagnosed with Stargardt disease 1 (7), cone-rod dystrophy type 3 (8), cone dystrophy (1), and retinitis pigmentosa 19 (1). Onset of symptoms occurred between 5 and 27 years of age (median age = 12.4 years). A total of 30 unique ABCA4 suspicious pathogenic variations were observed, including 18 missense mutations, seven frameshift mutations, two nonsense mutations, one canonical splice site mutation, one small in-frame deletion, and one insertion. Four novel ABCA4 variants were identified. Two novel frameshift variants, c.1290dupC (p.W431fs), and c.2967dupT (G990fs), were determined to be pathogenic. A novel missense variant c.G5761T (p.V1921L) was likely pathogenic, and another novel missense c.C170G (p.P57R) variant was of undetermined significance. All ABCA4 variants tested in this study inordinately changed the physico-chemical parameters and structure of protein based on in silico analysis.ConclusionABCA4-related IRD is genetically and clinically highly heterogeneous. Four novel ABCA4 variants were identified. This study will expand the spectrum of disease-causing variants in ABCA4, which will further facilitate genetic counseling.

scholarly journals Functional Analysis of Monocarboxylate Transporter 8 Mutations Identified in Patients with X-Linked Psychomotor Retardation and Elevated Serum Triiodothyronine

2007 ◽  
Vol 92 (6) ◽  
pp. 2378-2381 ◽  
Author(s):  
Jurgen Jansen ◽  
Edith C. H. Friesema ◽  
Monique H. A. Kester ◽  
Carmelina Milici ◽  
Maarten Reeser ◽  
...  
Keyword(s):  
Elevated Serum ◽  
Splice Site Mutation ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Missense Mutations ◽  
Wild Type ◽  
Site Mutation ◽  
Central Neurons ◽  
Serum T3 ◽  
Type 3

Abstract Context: T3 action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T3 uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T3 levels. Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T3. Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T3 uptake, 2) T3 metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry. Results: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8. Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T3 levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T3 in central neurons.

scholarly journals Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

2020 ◽  
Author(s):  
Riccardo Sangermano ◽  
Iris Deitch ◽  
Virginie G Peter ◽  
Rola Ba-Abbad ◽  
Emily M Place ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Early Onset ◽  
Joubert Syndrome ◽  
Phenotypic Correlation ◽  
Cone Dystrophy ◽  
Genetic Modifiers ◽  
Retinal Degenerations ◽  
Pathogenic Variants ◽  
Systemic Disorder ◽  
The Impact

Purpose: Pathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity. Methods: Targeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation. Results: Fourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers. Conclusions: The study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

scholarly journals The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3797-3804 ◽  
Author(s):  
Q Zhu ◽  
M Zhang ◽  
RM Blaese ◽  
JM Derry ◽  
A Junker ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Point Mutations ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Was Gene

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations.

Overlooking MMR deficiency in carriers of certain pathogenic variants by routine MSI and/or IHC testing in Lynch syndrome: Implications for a wider MMR deficiency testing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16107-e16107
Author(s):  
Marija Staninova Stojovska ◽  
Katerina Kubelka Sabit ◽  
Dzengis Jasar ◽  
Rubens Jovanovic ◽  
Nadica Matevska ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Positive Result ◽  
Splice Site Mutation ◽  
The Other ◽  
Sporadic Colorectal Cancer ◽  
Site Mutation ◽  
Potential Implication ◽  
Mmr Genes ◽  
Pathogenic Variants ◽  
Mmr Deficiency

e16107 Background: DNA mismatch repair (MMR) deficiency occurs in both inherited/sporadic colorectal cancer (CRC) and endometrial cancer, but it may also be found in some other types of cancer. At present, MMR status testing in clinical practice is recommended for all CRC patients in order to identify those who should be offered genetic testing for the Lynch syndrome (LS), inform disease prognosis, and guide therapeutic management.There are two commonly accepted methods for MMR deficiency analysis, one based on the detection of microsatellite instability (MSI) by PCR and the other based on the detection of protein expression of the MMR genes using immunohistochemistry (IHC). The objective of this study was to evaluate the concordance between IHC and MSI in tumors from 18 LS patients with known pathogenic germline variants in MMR genes (MLH1, MSH2, PMS2 and MSH6). Methods: The MSI testing was performed using the five gene Bethesda panel (BAT25, BAT26, D2S123, D5S346, D17S250) while the IHC testing was done with the use of a standard 4 antibody panel (MLH1, MSH2, PMS2 and MSH6). Results: High concordance of the two methods was observed in 13/18 (72.2%) patients, mainly with disruptive mutations in the МLH1, MSH2 and PMS2 genes. Inconsistent results were obtained in 5/18 (28.8%) patients, of whom two had a positive result only with the use of the PCR method [carriers of MLH1 c.62C > T (p.Ala21Val) and c.244A > G (p.Thr82Ala) missense variants], other two had a positive result only with IHC [carriers of MSH6 c.3514dupA (p.Arg1172LysfsTer5) and c.2384T > C (p.Ile795Thr)] and one patient had normal results using both methods (carrier of MSH6 c.457+1G > T splice site mutation that results in exon 3 skipping). A positive predictive value of either MSI or IHC used as a single methods for screening was 83.3%, which indicates that a substantial number of cases with MMR tumors can be misdiagnosed by using only either one or the other of these two methods. Conclusions: These results have a potential implication not only for LS screening in CRC patients, but also for the detection of the MMR deficiency in patients with various tumors that might benefit from the checkpoint inhibitor immunotherapy. The use of extended MSI NGS panels might provide a higher sensitivity for the detection of MMR deficiency compared to the standard MSI or ICH testing.

scholarly journals A founder splice site mutation underlies glycogen storage disease type 3 in consanguineous Saudi families

2014 ◽  
Vol 34 (5) ◽  
pp. 390-395 ◽  
Author(s):  
Sulman Basit ◽  
Omhani Malibari ◽  
Alia Mahmood Al Balwi ◽  
Firoz Abdusamad ◽  
Feras Abu Ismail
Keyword(s):  
Glycogen Storage Disease ◽  
Splice Site ◽  
Storage Disease ◽  
Splice Site Mutation ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Disease Type ◽  
Site Mutation ◽  
Type 3

scholarly journals The mutational spectrum of Hunter syndrome reveals correlation between biochemical and clinical profiles in Tunisian patients

2020 ◽  
Author(s):  
latifa chkioua ◽  
Oussama Grissa ◽  
Nadia Leban ◽  
Moez Gribaa ◽  
Hela Boudabous ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Dermatan Sulfate ◽  
Splice Site Mutation ◽  
Hunter Syndrome ◽  
Molecular Testing ◽  
Missense Mutations ◽  
Lysosomal Storage ◽  
High Concentration ◽  
Site Mutation ◽  
Mps Ii

Abstract Background: Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is an X-linked recessive lysosomal storage disorder resulting from deficient activity of iduronate 2-sulfatase (IDS) and the progressive lysosomal accumulation of sulfated glycosaminoglycans (GAGs). Methods: A diagnosis of MPS II or Hunter syndrome was performed based on the following approach after a clinical and paraclinical suspicion. Two biochemical and molecular tests were carried out separately and according to the availability of the biological material. Results: All patients in this cohort presented the most common MPS II clinical features. Electrophoresis of GAGs on a cellulose acetate plate in the presence of a high concentration of heparane sulfate showed an abnormal dermatan sulfate band in the patients compared with that in a control case. Furthermore, leukocyte IDS activity ranged from 0.00 to 0.75 nmol/h/mg of leukocyte protein in patients.Five previously reported mutations were identified in this study patients: one splice site mutation, c.240+1G>A; two missense mutations, p.R88P and p.G94D; a large deletion of exon 1 to exon 7; and one nonsense mutation, p.Q396*. In addition, two novel alterations were identified in the MPS II patients: one frame shift mutation, p.D450Nfs*95 and one nonsense mutation, p.Q204*. Additionally, five known IDS polymorphisms were identified in the patients: c.419-16 delT, c.641C>T (p.T214M), c.438 C>T (p.T146T), c.709-87G>A, and c.1006+38T>C.Conclusions: The high level of urine GAGs and the deficiency of iduronate 2-sulfatase activity was associated with the phenotype expression of Hunter syndrome. Molecular testing was useful for the patients’ phenotypic classification and the detection of carriers.

Detection of Ten New Mutations by Screening the Gene Encoding Factor IX of Danish Hemophilia B Patients

1995 ◽  
Vol 73 (05) ◽  
pp. 774-778 ◽  
Author(s):  
Marianne Schwartz ◽  
Jørgen Ingerslev ◽  
Elma Scheibel ◽  
Lise Rud Nielsen
Keyword(s):  
Point Mutations ◽  
Splice Site Mutation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Missense Mutations ◽  
Coding Region ◽  
Site Mutation ◽  
Gene Encoding ◽  
Base Pair Deletion ◽  
Wide Range

SummaryHemophilia B is caused by a wide range of mutations. In order to characterize the mutations among patients in Denmark, we have systematically screened the entire coding region, the promoter region and exon flanking sequences of the gene encoding factor IX using single strand conformation and heteroduplex analyses. Patients from 32 different families were examined, and point mutations (23 different) were found in all of them. Ten of the mutations have not been reported by others; they include a splice site mutation, a single base pair deletion, and missense mutations. Notably, the study contains a female patient and a previously described Leyden mutation. In ten families with sporadic cases of hemophilia B, all 10 mothers were found to be carriers. The origin of two of these mutations was established.

scholarly journals Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aliaa H. Abdelhakim ◽  
Avinash V. Dharmadhikari ◽  
Sara D. Ragi ◽  
Jose Ronaldo Lima de Carvalho ◽  
Christine L. Xu ◽  
...  
Keyword(s):  
Coenzyme Q ◽  
Clinical Manifestations ◽  
Missense Variant ◽  
Neurological Involvement ◽  
Cone Dystrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
End Stage

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

A Novel Splice Site Variant in FOXN1 in A Patient with Abnormal Newborn Screening for Severe Combined Immunodeficiency and Congenital Lymphopenia

2021 ◽  
Author(s):  
Ori Scott ◽  
Jenny Garkaby ◽  
Jessica Willett-Pachul ◽  
Yehonatan Pasternak
Keyword(s):  
Splice Site ◽  
Severe Combined Immunodeficiency ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Combined Immunodeficiency ◽  
Site Mutation ◽  
Cd8 Cells ◽  
Cell Counts ◽  
Epithelial Development ◽  
Whole Exome

Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations. Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency. Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation. Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother. Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up.

Identification of a novel candidate splice site mutation (0874+1G>A) in a type 3 von Willebrand disease patient

2007 ◽  
Vol 98 (08) ◽  
pp. 464-466 ◽  
Author(s):  
Inge Vrelust ◽  
Inge Vangenechten ◽  
Reinhard Schneppenheim ◽  
Marc Van der Planken ◽  
Alain Gadisseur
Keyword(s):  
Splice Site ◽  
Disease Patient ◽  
Splice Site Mutation ◽  
Von Willebrand Disease ◽  
Site Mutation ◽  
Type 3 ◽  
Von Willebrand
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