Genetics of Waardenburg Syndrome in Africa: A Systematic Review

Waardenburg syndrome (WS) represents a group of genetic conditions characterized by auditory and pigmentation defects. Pathogenic variants in <i>PAX3</i>, <i>MITF</i>, <i>SOX10</i>, <i>EDN3</i>, <i>EDNRB</i>, <i>SNAI2</i>, and <i>KITLG</i> genes have been associated with WS across multiple populations; a comprehensive study of WS in Africa has not yet been reported. We conducted a systematic review of clinical expressions and genetics of WS across Africa. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed, and the study protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews (2025 CRD420250655744). A literature search was performed on Google Scholar, PubMed, Scopus, Directory of Open Access Journals (DOAJ), Global Index Medicus, African-Wide Information, ScienceDirect, Connecting Repositories (CORE), and the Web of Science databases. We reviewed a total of 15 articles describing 84 WS cases, which showed no gender bias and a mean age at reporting of 17.5 years. Congenital, sensorineural, and profound hearing loss was described in most cases (66.7%; <i>n</i> = 56/84). WS type 2 (WS2), with characteristically no dystopia canthorum, is the predominant subtype (36.9%; <i>n</i> = 31/84). Pathogenic variants in four WS known genes, i.e., <i>PAX3</i> (13 families), <i>SOX10</i> (7 families), <i>EDNRB</i> (4 families), and <i>EDN3</i> (1 family), were reported in Morocco, Tunisia, and South Africa. One candidate gene (<i>PAX8</i>) was described in one family in Ghana. Two non-syndromic hearing loss (NSHL) genes (<i>BDP1</i> and <i>MYO6</i>) were reported in two separate families in South Africa, suggesting a possible phenotypic expansion. The highest number of WS cases was described in South Africa (38.1%; <i>n</i> = 32/84) and Tunisia (26.2%; <i>n</i> = 22/84). Gene variants were missense (27/43), deletion (7/43), splicing (5/43), nonsense (2/43), indel (1/43), and duplication (1/43), chiefly segregating in an autosomal dominant inheritance mode. There was no functional data to support the pathogenicity of putative causative variants. This review showed that WS2 is the most common in Africa. Variants in <i>PAX3</i> and <i>SOX10</i> were the predominant genetic causes. This study emphasizes the need to further investigate in-depth clinical characterization, molecular landscape, and the pathobiology of WS in Africa.