A Novel Tool for the Analysis and Detection of Copy Number Variants Associated with Haemoglobinopathies

Abstract

Several types of haemoglobinopathies are caused by copy number variants (CNVs). While diagnosis is often based on haematological and biochemical parameters, a definitive diagnosis requires molecular DNA analysis. In some cases, the molecular characterisation of large deletions/duplications is challenging and inconclusive and often requires the use of specific diagnostic procedures, such as multiplex ligation-dependent probe amplification (MLPA). Herein, we collected and comprehensively analysed all known CNVs associated with haemoglobinopathies. The dataset of 291 CNVs was retrieved from the IthaGenes database and was further manually annotated to specify genomic locations, breakpoints and MLPA probes relevant for each CNV. We developed IthaCNVs, a publicly available and easy-to-use online tool that can facilitate the diagnosis of rare and diagnostically challenging haemoglobinopathy cases attributed to CNVs. Importantly, it facilitates the filtering of available entries based on the type of breakpoint information, on specific chromosomal and locus positions, on MLPA probes, and on affected gene(s). IthaCNVs brings together manually curated information about CNV genomic locations, functional effects, and information that can facilitate CNV characterisation through MLPA. It can help laboratory staff and clinicians confirm suspected diagnosis of CNVs based on molecular DNA screening and analysis.

IthaPhen: An Interactive Database of Genotype-Phenotype Data for Hemoglobinopathies

“…First, we investigate phenotypic differences in deletional hereditary persistence of fetal hemoglobin (HPFH) and δβ‐thalassemia, two molecularly similar conditions characterized by elevated fetal hemoglobin (Hb F) levels. In heterozygotes, their diagnosis is challenging as it strongly depends on hematological indices and empirical differences in the Hb F levels 15 . Using case‐level data stored in IthaPhen, we performed a series of logistic regression models (http://links.lww.com/HS/A441) to demonstrate a quantitative approach in the diagnosis of the 2 conditions.…”

“…In heterozygotes, their diagnosis is challenging as it strongly depends on hematological indices and empirical differences in the Hb F levels. 15 Using case-level data stored in IthaPhen, we performed a series of logistic regression models (Suppl. File 2) to demonstrate a quantitative approach in the diagnosis of the 2 conditions.…”

Case report: Long-read sequencing identified a novel 14.9-kb deletion of the α-globin gene locus in a family with α-thalassemia in China

“…At present, the thalassemia carrier screening strategy in China mainly focus on 23 most common variants, which include three deletions (--SEA , -α 4.2 , -α 3.7 ), three SNVs in HBA1/2, and 17 SNVs/indels in HBB (He et al, 2014). In clinical study, occasionally the genotypes identified by conventional PCR-based methods are not well correlated well with the phenotypes, indicating the possibility of rare variations, which are beyond the detecting range of conventional methods (Aliyeva et al, 2018;Minaidou et al, 2022).…”