March 23, 2023

The Expanding Phenotype of ZTTK Syndrome Due to the Heterozygous Variant of SON Gene Focusing on Liver Involvement: Patient Report and Literature Review

Andrea Pietrobattista, Luca Della Volpe, Paola Francalanci, Lorenzo Figà Talamanca, Lidia Monti, Francesca Romana Lepri, Maria Sole Basso, Daniela Liccardo, Claudia Della Corte, Antonella Mosca, Tommaso Alterio, Silvio Veraldi, Francesco Callea, Antonio Novelli, Giuseppe Maggiore.

Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK, OMIM#617140) is an autosomal dominant genetic condition caused by heterozygous SON gene mutations that affect RNA splicing and cell cycle progression. SON haploinsufficiency could result in intron retention, exon skipping, and impact genes essential for organ development and metabolism. Developmental delay, brain abnormalities, facial dysmorphisms, eye problems, urogenital deviations, and craniosynostosis are among the predicted effects of pathogenic variations in the SON gene. The authors of the study reported de novo heterozygous SON variation identified during the examination of chronic liver disease (CLD) in the ZTTK syndrome patient. While consistent with other cases, this patient’s presentation underscores the importance of recognizing liver involvement in ZTTK syndrome, contributing to a deeper understanding of this rare disorder.


Read More on:

Biallelic truncating variants in children with titinopathy are a recognizable condition with distinctive muscular and cardiac characteristics.

This report describes five patients.


A 16-year-old male, born to healthy non-consanguineous parents with no genetic disease history, experienced developmental delays at 9 months. Psycho-motor rehab and school support aided milestones like walking at 16 months, speaking at around 3 years. At 5, he had vesicoureteral reflux surgery. At 12, abdominal ultrasound detected liver issues with normal liver function tests results. Four years later, worsening liver problems led to a Pediatric Hepatology Center referral, along with mild splenomegaly, ligamentous hyperlaxity, and facial dysmorphisms. Extensive diagnostics excluded common CLD causes while liver biopsy showed cirrhosis.


Following accepted practices, clinical exome sequencing was carried out on the proband’s and his parents’ genomic DNA. Sequencing was performed on a NovaSeq6000 platform. The target included coding exons with 25-base region extensions on both ends.  Results showed a mean 150× coverage for 97% of bases, specificity and sensitivity of 100%, and a quality score of more or equal to 30. The BaseSpace pipeline was employed to call the variations. Dragen Germline Enrichment was applied in variant calling. The Geneyx Analysis software was used for annotating variations and prioritizing candidate genes based on patient’s phenotype. The results revealed a pathogenic SON c.5751_5754delAGTT variant, suggesting ZTTK syndrome, which was confirmed by brain MRI.


In contrast to other ZTTK syndrome cases that exhibit recurrent phenotypic characteristics, this case demonstrated a distinct liver pathology including cirrhosis and spongiosis hepatis. The significance of genetic considerations in pediatric liver illnesses is highlighted by this surprising diagnosis made during an examination of CLD. It should be emphasized that liver involvement might happen even in the absence of abnormal liver function tests. It is also important to note that understanding the function of the SON gene in human development and its possible relationship to cancer and liver illness requires additional research. In conclusion, the authors suggested testing patients with SON variants for liver involvement because normal liver function tests may not completely rule out fibrosis.


Contact us for more information




Selected Videos

Geneyx Analysis Version 5.12 Release


Schedule Demo

Contact us to set a live demo

Contact Us

Whether you have general questions about our solutions or would like to schedule a demo or to suggest collaboration – our team is on hand for you.