Background/Objectives: Hereditary spastic paraplegia type 52 (SPG52) is a rare, inherited neurodevelopmental condition passed down in an autosomal recessive pattern. In this report, we describe two siblings from Rwanda who exhibited classic signs of the disorder, including progressive lower-limb spasticity, significant delays in motor development, and exaggerated deep tendon reflexes. Methods: Genetic testing through Whole-Exome Sequencing (WES) reveals a rare homozygous splice-site variant (NM_001128126.3:c.295-3C>A) in the AP4S1 gene. Results: Despite the severity of symptoms, both children responded positively to treatment with muscle relaxants and regular physiotherapy. Notably, MRI scans of the brain and spine showed no structural abnormalities. Conclusions: By documenting this case, we add to the growing understanding of SPG52, particularly within under-represented Sub-Saharan African populations, and underscore the critical role of early genetic testing in guiding timely diagnosis and intervention.

Background: Kleefstra syndrome (KS) is a rare neurodevelopmental disorder caused by haploinsufficiency of EHMT1; it is characterized by global developmental delay, intellectual disability, hypotonia, distinctive facial features, and variable congenital anomalies. Autistic features, behavioral abnormalities and severe speech impairment are frequently reported. However, molecularly confirmed cases of KS from Africa remain extremely limited, largely due to restricted access to genomic diagnostic infrastructures. Methods: We describe a 15-month-old patient from Rwanda presenting with neonatal hypotonia, global developmental delay, short stature, and characteristic dysmorphic facial features. Comprehensive clinical evaluation was performed, followed by trio-based exome sequencing to identify the underlying genetic cause of this neurodevelopmental disorder. Results: Exome sequencing identified a de novo heterozygous frameshift variant in EHMT1 (NM_024757.5: c.2871dup; p. Phe958Leufs*219), confirming the diagnosis of KS. Conclusions: This report presents the first molecularly confirmed case of KS in Rwanda. It highlights additional clinical features like bilateral 5th toe clinodactyly, short stature and absence of obesity in KS. There is a need to further delineate the study of EHMT1 and investigate the natural history of KS across different populations for optimal patient management and to reduce diagnostic odyssey. The diagnostic utility of exome sequencing for neurodevelopmental disorders needs to be strengthened, with strong emphasis on expanding genomic medicine to help diagnose rare diseases in resource-limited settings.

Background: Over three-quarters of the people living with hearing impairment (HI) live in low- and middle-income countries. However, Rwanda has limited data on the clinical profile of HI. Aim: We used community-based nationwide recruitment of participants to determine the etiology of early-onset (<7 years of age) HI in Rwanda. Methods: Participants were included after clinical examination, including audiological assessment by pure tone audiometry and/or auditory brainstem response. DNA was extracted from peripheral blood, and the entire coding region of GJB2 was interrogated using Sanger sequencing. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of the GJB6-D3S1830 deletion. Results: The participants were recruited from seven inclusive schools, one university teaching hospital, and four independent communities nationwide. We reviewed the clinical histories of 422 individuals affected by early-onset HI from 348 families and found that 21.18% (n = 89/422) was linked to early childhood meningitis infection while 51.23% (n = 216/422) was categorized as unknown HI etiology. Because of putative genetic causes, 82/348 (23.6%) families were reviewed and identified for genetic testing. Within the 82 families with potential genetic causes, 122 individuals were affected by HI, and 205 were unaffected. The male/female ratio of those enrolled for genetic investigations was 0.79 (n = 145/182). The mean age of diagnosis of HI was 4.3 ± 2.6 years. Most cases (89.36%, n = 109/122) reviewed were prelingual. Pedigree analysis suggested autosomal recessive inheritance in 46.3% (n = 38/82) of families. Most HI participants from familial cases had nonsyndromic HI (94.2%, n = 115/122). Waardenburg syndrome was found in three participants out of seven participants who presented with syndromic HI, while three other participants manifested signs of Usher syndrome and one with suspected Noonan syndrome. Molecular analysis did not find pathogenic variants in GJB2 or GJB6-D3S1830 deletion in any of the probands tested (n = 27/122; 22.13%) or 100 non-affected control participants. Conclusions: This study revealed an overall late diagnosis (mean at 4.3 years) of HI in Rwanda. Most cases were of unknown origin or putative environmental origin (76.4%), with meningitis predominating as the acquired cause of early-onset HI. Among cases of putative genetic etiology, nonsyndromic HI accounted for the large majority (94.2%). However, GJB2 and GJB6 pathogenic variants were not identified in the screened proportion of the cohort. This study calls for the implementation of neonatal hearing screening as well as reinforcement of immunization programs to reduce the burden of acquired early-onset HI in Rwanda. Additional genomic studies, ideally using exome sequencing for familial cases, are needed.