RTTN – Bilateral Generalized Polymicrogyria

Rotatin, encoded by RTTN, is a centrosomal protein implicated in centriole assembly, ciliogenesis, and neuronal migration. Biallelic RTTN variants cause a spectrum of neurodevelopmental disorders featuring microcephaly, short stature, intellectual disability, and cortical malformations, including polymicrogyria. Here, we focus on the association between RTTN and bilateral generalized polymicrogyria.

Autosomal recessive inheritance of RTTN variants underlies bilateral generalized polymicrogyria. A recent case report described a single proband presenting with bilateral generalized polymicrogyria, cerebellar hypodysplasia, multiple arachnoid cysts, microcephaly, short stature, and intellectual disability. The patient harbored novel compound heterozygous missense substitutions c.5500A>G (p.Asn1834Asp) and c.19A>G (p.Ile7Val), each inherited from an unaffected parent, with no additional affected relatives identified (1 proband) (PMID:38178912).

A comprehensive review of RTTN-related neurodevelopmental disorders encompassing 23 published and 5 unpublished individuals highlighted polymicrogyria in 8 subjects from 6 unrelated pedigrees, all carrying biallelic loss-of-function or missense variants, confirming recurrent involvement of RTTN in cortical malformations (PMID:30879067).

The variant spectrum includes missense, nonsense, splice-site, frameshift, and deep-intronic alleles. Notably, a recurrent truncating mutation, c.3705C>A (p.Tyr1235Ter), was reported in multiple individuals with polymicrogyria and microcephaly, demonstrating loss of rotatin function (PMID:30879067).

Functional assays in patient-derived fibroblasts revealed reduced primary cilia length and number, indicating impaired ciliogenesis in RTTN-deficient cells (PMID:29967526). In human cortical organoids engineered with the homozygous c.2953A>G (p.Arg985Gly) variant, neural stem cells exhibited cell cycle arrest, mitotic defects, and delayed neural rosette formation, recapitulating key features of cortical dysplasia (PMID:39680576).

Together, these data support a Moderate clinical validity for RTTN in bilateral generalized polymicrogyria, with consistent genetic segregation and concordant functional abnormalities. RTTN should be included in diagnostic gene panels for polymicrogyria to guide patient management and genetic counseling.

Key take-home: Autosomal recessive RTTN variants are a confirmed cause of bilateral generalized polymicrogyria, with molecular and cellular evidence supporting a defect in centriole and cilia function.

References

• Frontiers in Pediatrics • 2023 • Case Report: Novel biallelic moderately damaging variants in RTTN in a patient with cerebellar dysplasia. PMID:38178912
• Brain • 2019 • Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics. PMID:30879067
• Pediatric Research • 2018 • Functional characterization of biallelic RTTN variants identified in an infant with microcephaly, simplified gyral pattern, pontocerebellar hypoplasia, and seizures. PMID:29967526
• PLoS Genetics • 2024 • A Taybi-Linder syndrome-related RTTN variant impedes neural rosette formation in human cortical organoids. PMID:39680576

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