Spadmiss with basal ganglia calcification and multilocus genetic disease: a novel phenotypic expansion

SpADMiSS syndrome (SPOUT1-Associated Developmental delay, Microcephaly, Seizures, and Short stature) is a recently described autosomal recessive neurodevelopmental disorder caused by biallelic variants in SPOUT1/CENP-32. The phenotypic spectrum of this condition is still evolving. Reporting novel clinical features and complex genetic architectures is essential to refine genotype-phenotype correlations, particularly in consanguineous populations.

We describe a 5.5-year-old girl born to consanguineous parents who presented with refractory early-onset seizures, severe global developmental delay, growth failure, and microcephaly. Neuroimaging revealed marked cerebral atrophy and previously unreported bilateral basal ganglia calcification. The patient also developed bilateral cataracts requiring surgical intervention. Whole-exome sequencing identified a recurrent homozygous missense variant in SPOUT1/CENP-32 (c.292 G > A; p.Gly98Ser), confirming the diagnosis of SpADMiSS. In addition, homozygous pathogenic variants were detected in XYLT2 and EYS, indicating multilocus genetic disease.

This case expands the phenotypic spectrum of SpADMiSS by documenting basal ganglia calcification, a feature not previously reported in affected individuals. The presence of early-onset cataracts and ocular involvement is best explained by concurrent pathogenic variants in XYLT2 and EYS, illustrating a blended phenotype due to multilocus inheritance. These findings highlight the importance of comprehensive genomic analysis in consanguineous families to avoid misattribution of clinical features to a single genetic disorder.

We report a novel presentation of SpADMiSS syndrome associated with basal ganglia calcification and multilocus pathogenic variation. This case underscores the expanding neuroimaging phenotype of SPOUT1/CENP-32-related disease and emphasizes the critical role of whole-exome sequencing in accurately delineating complex phenotypes in consanguineous populations.