# Genetic Modifiers of Sickle Cell Anemia Phenotype in a Cohort of Angolan Children

## TL;DR

This study identifies genetic factors influencing sickle cell anemia severity in Angolan children, highlighting genes linked to disease variability.

## Contribution

The first investigation of SCA clinical variation in Angola using targeted sequencing to identify genetic modifiers.

## Key findings

- Candidate genes associated with vaso-occlusive crises and lower fetal hemoglobin were identified.
- Two SNPs in the BCL11A gene region are significantly linked to decreased fetal hemoglobin levels.
- A catalog of genetic modifiers in key pathophysiological pathways was generated for SCA phenotypic variability.

## Abstract

The aim of this study was to identify genetic markers in the HBB Cluster; HBS1L-MYB intergenic region; and BCL11A, KLF1, FOX3, and ZBTB7A genes associated with the heterogeneous phenotypes of Sickle Cell Anemia (SCA) using next-generation sequencing, as well as to assess their influence and prevalence in an Angolan population. Hematological, biochemical, and clinical data were considered to determine patients’ severity phenotypes. Samples from 192 patients were sequenced, and 5,019,378 variants of high quality were registered. A catalog of candidate modifier genes that clustered in pathophysiological pathways important for SCA was generated, and candidate genes associated with increasing vaso-occlusive crises (VOC) and with lower fetal hemoglobin (HbF) were identified. These data support the polygenic view of the genetic architecture of SCA phenotypic variability. Two single nucleotide polymorphisms in the intronic region of 2q16.1, harboring the BCL11A gene, are genome-wide and significantly associated with decreasing HbF. A set of variants was identified to nominally be associated with increasing VOC and are potential genetic modifiers harboring phenotypic variation among patients. To the best of our knowledge, this is the first investigation of clinical variation in SCA in Angola using a well-customized and targeted sequencing approach.