A Data-Driven Approach to Carrier Screening for Common Recessive Diseases

Abstract

Genetic screening is an advanced tool for reducing recessive disease burden. Nowadays, it is still unclear as to the number of genes or their variants that are necessary for effective screening. This paper describes the development of a carrier screening custom panel for cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss consisting of 116 variants in the CFTR, PAH, SERPINA1, and GJB2 genes. The approach is based on the cheapest and fastest method, on using a small number of genes, and on the estimation of the effectiveness of carriers’ detection. The custom panel was tested on a population-based cohort that included 1244 participants. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The frequency of heterozygotes in the Russian population was 16.87% or 1:6 (CI95%: 14.76–19.00% by Clopper-Pearson exact method): in CFTR—2.81% (1:36), PAH—2.33% (1:43), SERPINA1—4.90% (1:20), and GJB2—6.83% (1:15). The data on allele frequencies were obtained for the first time on a Russian population. The panel allows us to identify the vast majority of carriers of recessive diseases in the population. It is an effective approach to carrier screening for common recessive diseases.

Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

“…Moreover, this whole-exome study demonstrated the overrepresentation of several disease-causing variants for Mendelian disorders, such as phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), and the kyphoscoliosis type of Ehlers-Danlos syndrome (FKBP14, rs542489955). For the Russian population, however, pathogenic variant frequencies were reported mostly for relatively small cohorts including patients and their families and targeted at specific genes and disorders, for example, familial hypercholesterolemia (Meshkov et al, 2021;Miroshnikova et al, 2021); cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss (Kiseleva et al, 2020;Petrova et al, 2020); cardiomyopathy (Marakhonov et al, 2019;Zaklyazminskaya et al, 2019;Kulikova et al, 2021;Shestak et al, 2021); and breast and ovarian cancer (Brovkina et al, 2018;Solodskikh et al, 2019).…”

Molecular classification of blood and bleeding disorder genes

“…There is an emphasis on the role of heterozygous carriers in AR disease that was the basis for the concept of premarital screening programs especially in consanguineous populations 26,27 . The concept is also included in prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) for monogenic inherited disorders 28,29 , and expanded carrier testing (ECT), a term that can be extended to include screening for genes involved in complex or multigene disorders 30,31 .…”

Management of biobanking for medical genetics research

“…В связи с этим всего за несколько лет количество научных проектов, проводимых в сотрудничестве с Биобанком, значительно увеличилось. Технологии биобанкирования и стандартизация всех этапов пробоподготовки и информационного сопровождения в виде баз данных позволяют проводить широкомасштабные генетические исследования [26][27][28][29]. Другой пример возрастающей важности биобанков как источника биообразцов необходимого количества и качества -это развитие протеомики, метаболомики, липидомики и других омикс-технологий, которые могут дать информацию о развитии и прогнозе заболеваний, а также о возможных реакциях на определенный образ жизни (питание и др.)…”