A Putative HACE۱ Founder Mutation in Iranian Patients with Spastic Paraplegia and Psychomotor Retardation with or Without Seizures: Five Cases and Literature Review

Background: Biallelic pathogenic variants in the HACE۱ gene are responsible for the ultra-rare neurodevelopmental disorder Spastic Paraplegia and Psychomotor Retardation with or without Seizures (SPPRS). This study investigates the genetic basis of SPPRS in patients from two unrelated Iranian families and provides a comprehensive review of all reported cases harboring HACE۱ variants. Methods: We performed whole exome sequencing (WES) on the probands of the two families, each from a consanguineous marriage. The identified variant was validated, and its co-segregation was confirmed using Sanger sequencing. To investigate a common ancestral origin, we subsequently conducted haplotype analysis, runs of homozygosity (ROH) mapping and mutation age estimation. Results: WES identified the same homozygous nonsense variant HACE۱:c.۱۳۹۶CT (p.Gln۴۶۶Ter) in both probands as the underlying cause. Sanger sequencing confirmed that this variant co segregated with the disease in both families. Subsequent analyses revealed a shared ancestral haplotype within a ~۶.۶ Mb run of homozygosity (ROH) containing the HACE۱ gene, confirming a common origin for the mutation, which was estimated to have arisen approximately ۱۰.۳ generations ago (roughly ۲۵۰ years). Furthermore, a comprehensive review of all reported cases identified delayed psychomotor development, intellectual disability, hypotonia, spasticity, structural brain abnormalities, motor disorders and speech impairment as the most prevalent clinical features of this syndrome. Conclusion: Our findings suggest that the HACE۱:c.۱۳۹۶CT variant is a founder mutation within the Iranian population, representing the first report of SPPRS-causing variants in this population and the first founder mutation for this gene reported worldwide. This study expands the known genetic and clinical spectrum of the disorder and highlights phenotypic heterogeneity, even among patients sharing the same genotype. This discovery has crucial clinical implications, enabling the development of targeted screening strategies and improving genotype-phenotype correlations, thereby facilitating more accurate genetic counseling for at-risk families.

کلیدواژه ها:

HACE۱ ، Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) ، spasticity ، founder mutation ، genotype- phenotype correlation ، Iran