Dataset Information

Functional Characterization of ABCA4 Missense Variants Aids Variant Interpretation and Phenotype Prediction in Patients With ABCA4-Retinal Dystrophies.

ABSTRACT:

Purpose

Biallelic pathogenic variants in the gene encoding the ATP-binding cassette transporter ABCA4 are the leading cause of irreversible vision loss in inherited retinal dystrophies (IRDs). Interpretation of ABCA4 variants is challenging, due to cis-modifying and hypomorphic variants. We have previously detected 10 missense variants of unknown significance (VUS) in patients with suspected ABCA4-retinal dystrophies (ABCA4-RDs) in Norway. In this study, we functionally characterized the VUS to aid interpretation of the variants and to determine if they are associated with the disease.

Methods

The ABCA4 VUS were expressed in HEK293T cells and the ABCA4 expression level and ATPase activity were determined and correlated with the patients' phenotype. The functional data further used for reclassification of the VUS following the American College of Medical Genetics and Genomics (ACMG) guidelines.

Results

Of the 10 VUSs, 2 variants, Cys205Phe and Asn415Thr, were categorized as functionally severe. The age at presentation in the 2 patients carrying these variants was divergent and seemed to be driven by the patients' second pathogenic variants Gly1961Glu and c.5461-10T>C, respectively. Three variants, Val643Gly, Pro799Leu, and Val1433Ile were categorized as functionally moderate, and were found in patients with intermediate/late age at presentation. The remaining five variants were categorized as functionally normal/mild. Based on our data, c.614G>T p.(Cys205Phe), c.1244A>C p.(Asn415Thr), and c.2396C>T p.(Pro799Leu) were reclassified to (likely) pathogenic, while 4 of the functionally normal/mild variants could be reclassified to likely benign.

Conclusions

Functional analyses of ABCA4 variants are a helpful tool in variant classification and enable us to better predict the disease severity in patients with ABCA4-RDs.

SUBMITTER: Aslaksen S

PROVIDER: S-EPMC11305421 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Functional Characterization of ABCA4 Missense Variants Aids Variant Interpretation and Phenotype Prediction in Patients With ABCA4-Retinal Dystrophies.

Aslaksen Sigrid S Aukrust Ingvild I Molday Laurie L Holtan Josephine Prener JP Jansson Ragnhild Wivestad RW Berland Siren S Rødahl Eyvind E Bredrup Cecilie C Bragadóttir Ragnheiður R Bratland Eirik E Molday Robert S RS Knappskog Per Morten PM

Investigative ophthalmology & visual science 20240801 10

<h4>Purpose</h4>Biallelic pathogenic variants in the gene encoding the ATP-binding cassette transporter ABCA4 are the leading cause of irreversible vision loss in inherited retinal dystrophies (IRDs). Interpretation of ABCA4 variants is challenging, due to cis-modifying and hypomorphic variants. We have previously detected 10 missense variants of unknown significance (VUS) in patients with suspected ABCA4-retinal dystrophies (ABCA4-RDs) in Norway. In this study, we functionally characterized the ...[more]

PMID: 39087934

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Project description:In this study, patients with inherited retinal dystrophies (IRDs) who visited Ningxia Eye Hospital from January 2015 to September 2023 were analyzed. Through Whole Exome Sequencing (WES) and Sanger verification, 17 probands carrying homozygous variants were detected. The association between the genotype and clinical phenotype of patients with homozygous variants was analyzed. Among all the patients, 3 patients (17.6%) had a family history of consanguineous marriage, and the onset age of 5 patients(29.4%) was less than 10 years. According to 12 patients (70.6% ), they had the best corrected visual acuity (monocular) < 0.3. 3 were blind, 9 with moderate to severe visual impairment, and 2 with mild visual impairment. 16 homozygous variants were detected in 9 different genes, of which 7 were novel homozygous variants, including frameshift variants, missense variants, and a copy number variant. These variants are related to clinical phenotypes such as Usher syndrome type II (USH2), Stargardt disease (STGD), retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and Bardet-Biedl syndrome (BBS) respectively. The results of the study indicate that more than 80% of persons with homozygous variant originated from non-consanguineous families, emphasizing the significance of genetic screening for individuals who lack a family history of consanguineous marriage and no obvious clinical phenotypes, but who may carry genetic pathogenic variants for genetic diseases. Furthermore, by analyzing the genotypes and clinical phenotypes of IRD patients from these 17 Chinese families, we have expanded the spectrum of variants in known pathogenic genes for IRDs and the range of clinical phenotypes associated with variants in these genes. We have identified couples at high risk of having affected offspring and individuals with moderate to severe IRDs, providing a basis for genetic counseling, reproductive decision-making, disease prevention, and management. Our findings highlight the association between homozygous variants and more severe clinical phenotypes within these families, thus laying the groundwork for future genetic screening and intervention strategies.

Dataset Information

Functional Characterization of ABCA4 Missense Variants Aids Variant Interpretation and Phenotype Prediction in Patients With ABCA4-Retinal Dystrophies.

Purpose

Methods

Results

Conclusions

Publications

Functional Characterization of ABCA4 Missense Variants Aids Variant Interpretation and Phenotype Prediction in Patients With ABCA4-Retinal Dystrophies.

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