SON – Zhu‐Tokita‐Takenouchi‐Kim Syndrome

Zhu‐Tokita‐Takenouchi‐Kim (ZTTK) syndrome is an autosomal dominant multisystem developmental disorder characterized by global developmental delay, intellectual disability, hypotonia, seizures, facial dysmorphism, and congenital anomalies. Pathogenic heterozygous loss-of-function variants in SON underlie ZTTK syndrome through haploinsufficiency of a key pre-mRNA splicing regulator. The disorder has been reported in over 94 unrelated probands across more than ten independent studies, with all variants arising de novo and cosegregating with disease phenotype ([PMID:34521999], [PMID:34331327]).

Genetic evidence includes numerous truncating variants distributed throughout SON, most commonly frameshift and nonsense changes. A recurrent four–base-pair deletion c.5753_5756del (p.Ala1340GlnfsTer26) has been observed in at least 13 individuals ([PMID:34521999]). Novel variants such as c.394C>T (p.Gln132Ter) have been independently reported, expanding the mutational spectrum ([PMID:31557424]). To date, over 100 loss-of-function alleles have been catalogued, reaching the ClinGen genetic evidence cap for dominant conditions.

Clinically, affected individuals present in infancy with severe growth and psychomotor delay, absent or limited speech, and characteristic facial features. Seizures and hypotonia are frequent, and additional findings may include structural brain anomalies, cardiac defects, and feeding difficulties. Penetrance is complete, though phenotypic expressivity varies between individuals, even among carriers of the same recurrent variant.

Functional assays support a haploinsufficiency mechanism: SON knockdown in neuronal cell lines disrupts proper splicing of critical neuronal genes, notably PRRT2, leading to premature termination codons and reduced transcript levels ([PMID:37057295]). Downregulation of SON similarly impairs global splicing fidelity, recapitulating cellular defects observed in patient-derived samples.

No studies to date have refuted the association; all evidence converges on SON haploinsufficiency as the pathogenic driver of ZTTK syndrome. Additional functional work, including animal models or rescue experiments, may further characterize tissue-specific effects but is not required for clinical utility.

Key Take-home: Heterozygous loss-of-function variants in SON cause a definitive form of ZTTK syndrome via haploinsufficiency, supporting inclusion of SON in diagnostic neurodevelopmental gene panels.

References

• Molecular genetics & genomic medicine • 2019 • Clinical and genetic analysis of ZTTK syndrome caused by SON heterozygous mutation c.394C>T. PMID:31557424
• American journal of medical genetics. Part A • 2021 • ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature PMID:34331327
• European journal of human genetics : EJHG • 2022 • Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON PMID:34521999
• Neurology. Genetics • 2023 • SON-Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine: Putative Role of PRRT2 PMID:37057295

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