Cascade testing is the process of offering genetic counselling and testing services to at risk family members of a patient/proband with a genetic disorder. Cascade testing allows family members to understand their risk of developing the phenotype, undertake risk reduction strategies and plan their reproductive choices. Cascade carrier screening, offered to asymptomatic family members, aims to identify male and female carriers of autosomal recessive disorders and female carriers of X-linked recessive traits with the aim of mitigating unknowingly passing the pathogenic variant to their offspring. Typically, in a family with sickle cell, haemophilia A or haemophilia B, phenotypically affected members undergo diagnostic testing in childhood due to development of symptoms. Carriers of sickle cell or haemophilia in an affected family may escape screening as they are asymptomatic, out of fear or may not have received adequate genetic counselling.

In affected families, genetic counselling and cascade screening/testing should be provided to all at risk, allowing family members to opt out. Cascade testing for adult-onset disease, that lack childhood intervention, should be deferred to adulthood to allow autonomy to either opt-in or opt-out of undergoing genetic testing. Factors affecting uptake of cascade testing include; availability of genetic practitioners and established genetic clinical care pathways; healthcare worker and patient awareness on heritability of the disorder; provision of genetic counselling and testing to proband; disclosure on heritability to family members; family acceptance for genetic testing; penetrance and severity of the phenotype and existing preventive and treatment strategies for the phenotype; availability and cost of genetic tests; societal, employment and insurance discrimination against persons with genetic disorders; privacy laws limiting sharing of patient information. Overall reported rates of cascade testing approximate 5%-30% of at risk relatives; closing this cascade gap offers a potential interventional approach to improve outcomes for genetic disorders and prevention of genetic disorders in the progeny. ^{1 , 2} Higher rates of cascade testing have been reported in actionable disorders where an intervention or treatment exists such as hereditary breast and ovarian cancer syndrome where 30-40% of relatives undergo genetic testing. ^{3 , 4} Huntington’s disease, a devastating neurological disorder with no known preventive strategies or cure, has traditionally reported very low uptake of cascade testing of about 5-25%. ^{5 – 7} Screening uptake is promoted by perceived benefits to self, family members and to inform reproductive choices, with barriers attributable to perceived irrelevance of testing, lack of knowledge and intention to undergo genetic testing in the future. ^{1 , 8 , 9} In African populations, screening challenges are compounded by limited access to molecular diagnostic facilities and traditional beliefs on the origins of familial disorders. ¹⁰

There is a paucity of African studies evaluating cascade testing for genetic disorders. Sickle cell is the commonest monogenic disorder among Africans. In Kenya, an estimated 14,000 people have sickle cell disease and 5,500 have haemophilia and is associated with increased morbidity, mortality and health related costs. ^{11 , 12} Uptake of genetic testing in Kenyan families continues to grow with increased access to molecular diagnostics, government led initiatives and community awareness. Acceptance of newborn screening for sickle cell disease has been found to be over 99% in malaria endemic regions of Kenya. ¹³

Study design: Cross-sectional descriptive health worker administered study.

Study population: A hospital-based survey of asymptomatic adult-at-risk first degree relatives of sickle cell or haemophilia proband attending the ambulatory haematology clinic at Kenyatta National Hospital. The clinic attends to approximately 8 haemophilia and 25 sickle cell patients monthly. Only one family member in the kindred was recruited. The sample size was derived from estimating the proportion anticipated to be recruited within the study period and meet the study objectives. Convenience recruitment was undertaken from May 2025 to July 2025.

Questionnaire design: The questionnaire was adapted with permission from a cystic fibrosis study undertaken by McLaren et al. in Australia. ⁸ Their study aimed to evaluate the barriers and promoters of cascade carrier screening following newborn genetic diagnosis of cystic fibrosis. It contained 8 domains; Sociodemographic (5 questions), relationship to cystic fibrosis proband (3 questions), knowledge about cystic fibrosis (13 questions), feelings about undergoing genetic carrier screening for cystic fibrosis (5 questions), factors influencing genetic carrier testing for cystic fibrosis (13 questions), barriers to genetic carrier testing for cystic fibrosis (17 questions), undergone genetic carrier testing for cystic fibrosis (3 questions), current or future progeny (3 questions).

The study recruited 67 first degree relatives of sickle cell and 21 first degree relatives of haemophilia probands. Majority of participants were parent to the proband (97% for sickle cell; 78% for haemophilia).

Questions assessed knowledge of genetic disorder afflicting the proband. Majority knew that the disease was inherited (94% sickle cell, 86% haemophilia). Few participants thought that carriers manifest the phenotype, with the majority aware that carrier parents may have unaffected progeny.

Knowledge was assessed using 18 questions which were scored 2-correct response, 1-unsure, 0- wrong response, with a minimum total score of 0 and maximum total score of 36. Blooms’ cut-off score was employed, with <60% low, 60%–80% moderate and >80% high score. High knowledge was found in only 33% of sickle cell and haemophilia participants.

The majority of the participants in the sickle cell and haemophilia arm had a good attitude and feeling towards undertaking genetic testing.

Participants were more likely to undergo genetic testing if a family member had the genetic disease, for current or future pregnancies, if the test was free, if the doctor suggested it and because they desired to have healthy babies.

Participants were less likely to undergo genetic testing in advanced maternal/paternal age, to avoid being blamed for passing on mutation to the offspring, if unsure that their genetic information would be kept private and if they perceived themselves as healthy.

This study set out to determine the promoters and barriers to cascade testing in families with sickle cell or haemophilia. Despite over 80% of participants being parents and caregiver to a child with the inherited disorder, only 33% had good knowledge on the inheritance patterns of the disorders. Low level of knowledge has also been demonstrated in other studies of sickle cell and haemophilia families, which impact decision-making on treatment and reproductive options. ^{14 , 15} Although the desire to have healthy offspring in future was a promoter to uptake of genetic testing, only 1 in 5 of the participants in our study had undergone genetic testing. Sickle cell and haemophilia, being childhood onset disorders, warrant neonatal or infant diagnosis to mitigate against severe manifestation of phenotype. Our findings demonstrated that only 1 in 3 first degree relatives, majority of whom were minors, had undergone genetic testing. Similarly, low rates of cascade testing of 5%-30% have been reported elsewhere. ^{1 , 2} Family testing provides an opportunity for early diagnosis and enrollment into care, allaying of anxiety for the unaffected and informing on current and future reproductive choices, as demonstrated in Gambia study conducted among siblings of sickle cell, with 19% being diagnosed with homozygous sickle cell and 47% heterozygous carriers. ¹⁶

This study identified several promoters of the uptake of cascade carrier screening, with the majority likely to undergo screening if a family member had been diagnosed with the condition and to inform on current or future pregnancies. Cost of testing emerged as a barrier to testing, with the majority of participants likely to get tested if the test was free, consistent with other studies that have demonstrated financial barriers to participating in cascade screening programs. ¹⁷ Recommendation of testing by healthcare providers positively influenced uptake of testing, an indication of the trust placed in clinicians as gatekeepers of genetic information. ¹⁸ Another promoter to testing was the desire to have healthy progeny, a finding consistent with other studies which demonstrated a strong desire to manage genetic risk for the benefit of the offspring as a driver for testing. ¹⁹

Participants were less likely to undergo genetic testing if they were of advanced maternal or paternal age, to avoid being blamed for passing on a genetic mutation to offspring, if they perceived themselves as healthy and if unsure that their genetic information would be kept private. Other works have demonstrated that older individuals perceived limited benefits as reproductive decisions are considered complete. ²⁰ Blame and stigma associated with genetic conditions been also documented elsewhere as a barrier to testing. ²¹ This stigma is compounded by privacy concerns, as individuals eligible for cascade screening often worry about misuse of their genetic information and the risk of discrimination. ²²

Cascade testing plays a critical role in the early detection and management in families identified to be at risk of a genetic disorder. Despite the high cost of genetic testing, it remains a cost-effective strategy in improving outcomes of genetic disorders through early diagnosis and initiation of care, reducing morbidity and mortality and informing on reproductive choices. Our study highlights the existing gaps in Kenyan families affected by common genetic disorders. Closing these gaps remains a critical step in the management of genetic disorders in our communities.

Despite knowledge of benefits, rates of cascade testing remain low in families of sickle cell and haemophilia. Interventions to enhance rates of family testing are needed.

Ethical approval was obtained from the Kenyatta National Hospital/University of Nairobi Ethics Review Committee (P416/05/2024). Written informed consent was obtained prior to recruitment in either Swahili or English languages.

Written informed consent for publication of the participants details was obtained from the participants.