Identification of a putative founder effect involving the HACE1:c.1396C>T variant in two Iranian families and review of reported cases.

backgroundBiallelic pathogenic variants in the HACE1 gene cause the ultra-rare neurodevelopmental disorder, Spastic Paraplegia and Psychomotor Retardation with or without Seizures (SPPRS). We identified a recurrent HACE1 variant in two unrelated, consanguineous Iranian families and investigated its potential founder origin, alongside a review of all reported HACE1-related cases.

methodsWhole exome sequencing (WES) was performed on the probands, and the variant was confirmed and segregated by Sanger sequencing. To assess a shared ancestral origin, we conducted runs of homozygosity (ROH) mapping, haplotype analysis, and mutation age estimation.

resultsBoth probands carried the same homozygous nonsense variant HACE1 (NM_020771.4:c.1396 C > T; p.Gln466Ter), which co-segregated with the disease in both families. ROH and haplotype analyses revealed a shared ~ 6.6 Mb homozygous region encompassing HACE1, consistent with a possible founder effect. The variant was estimated to have arisen approximately 10.3 generations ago (~ 250 years). Furthermore, review of previously reported HACE1-related cases indicated that delayed psychomotor development, intellectual disability, hypotonia, spasticity, brain abnormalities, motor disorders, and speech impairment are the most prevalent features.

conclusionOur findings support a putative founder effect, suggesting that the HACE1:c.1396C> T variant likely represents a founder variant within the Iranian population and, to our knowledge, mark the first report of SPPRS-causing variants from Iran. Beyond expanding the known genetic spectrum, this study highlights phenotypic heterogeneity, even among patients sharing the same genotype, and further characterizes the clinical variability and phenotypic spectrum of the disorder, thereby aiding more accurate diagnosis and genetic counseling for at-risk families.