Molecular genetic diagnosis of Stargardt disease

Chernov

2023

JPM

Today, whole-exome sequencing (WES) is used to conduct the massive screening of structural and regulatory genes in order to identify the allele frequencies of disease-associated polymorphisms in various populations and thus detect pathogenic genetic changes (mutations or polymorphisms) conducive to malfunctional protein sequences. With its extensive capabilities, exome sequencing today allows both the diagnosis of monogenic diseases (MDs) and the examination of seemingly healthy populations to reveal a wide range of potential risks prior to disease manifestation (in the future, exome sequencing may outpace costly and less informative genome sequencing to become the first-line examination technique). This review establishes the human genetic passport as a new WES-based clinical concept for the identification of new candidate genes, gene variants, and molecular mechanisms in the diagnosis, prediction, and treatment of monogenic, oligogenic, and multifactorial diseases. Various diseases are addressed to demonstrate the extensive potential of WES and consider its advantages as well as disadvantages. Thus, WES can become a general test with a broad spectrum pf applications, including opportunistic screening.

Section: Population Genetic Researches For Monogenic Diseasessupporting

confidence: 89%

Human Exome Sequencing and Prospects for Predictive Medicine: Analysis of International Data and Own Experience

Chernov

2023

JPM

“…Results of the prevalence analysis are summarized in Table 2. 12 genes passed our filtering criteria, with the following disorders being the most prevalent: (a) Stargardt disease (with ABCA4, MIM#601691, as the major gene, as also reported previously (Sheremet et al, 2017), incidence at least 1:3226), (b) cystic fibrosis (CFTR, MIM#602421, with the F508del (7:117199644:ATCT>A) mutation being the dominant variant), estimated incidence 1:5263, (c) phenylketonuria (PAH gene, incidence of up to 1:5556), (d) hepatic lipase deficiency (LIPC, MIM#151670, 1:10000, with one pathogenic variant rs113298164), and (e) tyrosinase-negative oculocutaneous albinism (TYR, 1:13158). Remarkably, our estimates of cystic fibrosis, galactosemia, and phenylketonuria incidence were concordant with previous gene-level estimates (Abramov, Kadochnikova, Yakimova, Belousova, Maerle, Sergeev, Ragimov, Donnikov, & Trofimov, 2015, Abramov, Belousova, Kadochnikova, Ragimov, & Trofimov, 2017.…”

Section: T a B L Ementioning

confidence: 76%

Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia

Barbitoff

Skitchenko

Poleshchuk

et al. 2019

Molec Gen & Gen Med

BackgroundAllele frequency data from large exome and genome aggregation projects such as the Genome Aggregation Database (gnomAD) are of ultimate importance to the interpretation of medical resequencing data. However, allele frequencies might significantly differ in poorly studied populations that are underrepresented in large‐scale projects, such as the Russian population.MethodsIn this work, we leveraged our access to a large dataset of 694 exome samples to analyze genetic variation in the Northwest Russia. We compared the spectrum of genetic variants to the dbSNP build 151, and made estimates of ClinVar‐based autosomal recessive (AR) disease allele prevalence as compared to gnomAD r. 2.1.ResultsAn estimated 9.3% of discovered variants were not present in dbSNP. We report statistically significant overrepresentation of pathogenic variants for several Mendelian disorders, including phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), kyphoscoliosis type of Ehlers‐Danlos syndrome (FKBP14, rs542489955), and several other recessive pathologies. We also make primary estimates of monogenic disease incidence in the population, with retinal dystrophy, cystic fibrosis, and phenylketonuria being the most frequent AR pathologies.ConclusionOur observations demonstrate the utility of population‐specific allele frequency data to the diagnosis of monogenic disorders using high‐throughput technologies.

“…Independent analysis of molecular genetic causes of 54 patients from Russia with Stargardt's disease showed 5 patients (in 9% of cases) with the presence of this complex allele [14].…”

Section: Discussionmentioning

confidence: 99%

Major Contribution of c.[1622T>C;3113C>T] Complex Allele and c.5882G>A Variant in ABCA4-Related Retinal Dystrophy in an Eastern European Population

Kadyshev,

Alekseeva,

Strelnikov

et al. 2023

IJMS

Inherited retinal diseases (IRDs) constitute a prevalent group of inherited ocular disorders characterized by marked genetic diversity alongside moderate clinical variability. Among these, ABCA4-related eye pathology stands as a prominent form affecting the retina. In this study, we conducted an in-depth analysis of 96 patients harboring ABCA4 variants in the European part of Russia. Notably, the complex allele c.[1622T>C;3113C>T] (p.Leu541Pro;Ala1038Val, or L541P;A1038V) and the variant c.5882G>A (p.Gly1961Glu or G1961E) emerged as primary contributors to this ocular pathology within this population. Additionally, we elucidated distinct disease progression characteristics associated with the G1961E variant. Furthermore, our investigation revealed that patients with loss-of-function variants in ABCA4 were more inclined to develop phenotypes distinct from Stargardt disease. These findings provide crucial insights into the genetic and clinical landscape of ABCA4-related retinal dystrophies in this specific population.