Novel biallelic CDK9 variants are associated with retinal dystrophy without CHARGE-like malformation syndrome - Brief Communication

Sep 29, 2026

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The study investigates how cyclin-dependent kinase 9 (CDK9) variants influence disease phenotype, focusing on retinal dystrophy. CDK9 normally phosphorylates the C-terminal domain of RNA polymerase II to regulate transcription, and biallelic CDK9 deficiency had previously been linked to a CHARGE-like malformation syndrome with vision-threatening retinal dystrophy. Here, a female patient with biallelic CDK9 variants is described: trio-based whole-exome sequencing identifies a de novo allele, p.P321S, producing compound heterozygous states (p.A288T plus p.P321S). The work suggests retinal dystrophy may occur with or without CHARGE-like features depending on combined kinase activity levels.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages7

Reading Time18 min

AccessFree to download

Introduction

CHARGE syndrome and CDK9 background

Case report

Clinical description

Ophthalmic phenotypes (Figure 1)

[www.nature.com/jhg](www.nature.com/jhg) BRIEF COMMUNICATION OPEN Novel biallelic CDK9 variants are associated with retinal dystrophy without CHARGE-like malformation syndrome Sachiko Nishina 1,8 ✉ , Kaoruko Torii2,8, Shizuka Ishitani3,8, Tomoyo Yoshida1, Maki Fukami 4, Kenji Kurosawa5, Kenjiro Kosaki6, Hirotomo Saitsu 7, Tohru Ishitani 3 and Yoshihiro Hotta 2 © The Author(s) 2025 | | Cyclin-dependent kinase 9 (CDK9) phosphorylates the C-terminal domain of RNA polymerase II (RNAPII) to regulate transcription. Previously, we reported that an 8-year-old boy with the biallelic CDK9 variants p.A288T and p.R303C exhibited a CHARGE-like malformation syndrome in which retinal dystrophy was a distinguishing feature. This dystrophy was caused by the decreased CDK9 kinase activity associated with these variant alleles [wild-type (WT) > A288T > R303C] . In this study, we describe a female patient who also bears biallelic CDK9 variants but displays retinal dystrophy without a CHARGE-like malformation syndrome. Trio-based whole-exome sequencing identiﬁed a new variant CDK9 allele, p.P321S, that occurred de novo in the patient. As a result, this female patient displayed compound heterozygous variants composed of the p.A288T CDK9 variant of maternal origin plus the novel p.P321S variant. With respect to reduced kinase activity, the new variant could be ranked as WT > P321S > A288T. Thus, our study raises a possibility that retinal dystrophy can arise with or without a CHARGE-like malformation syndrome depending on the level of | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | kinase activity associated with the combination of variant CDK9 alleles present. | | | | | Journal of Human Genetics (2026) 71:97–103; [https://doi.org/10.1038/s10038-025-01395-1](https://doi.org/10.1038/s10038-025-01395-1) | | | | | | INTRODUCTION Cyclin-dependent kinase 9 (CDK9) binds to cyclin T1 to form the positive transcription elongation factor b complex, which regulates transcription [1] . A major target of CDK9 kinase activity is the C-terminal domain of RNA polymerase II. Because of its essential role in numerous cellular responses, CDK9 is evolutionarily well conserved from yeast to zebraﬁsh to humans. In the context of human disease, hyperactivation of CDK9 leads to the development of various cancers, including acute myeloid leukemia. CDK9 has thus been deemed an attractive target for new cancer therapies. However, the precise functions of CDK9 inhuman physiological processes such as morphogenesis are still not fully understood. Filling such gaps in our knowledge of CDK9 biology is essential for the rational design of new treatments that will not impose harmful side-effects. CHARGE syndrome (CS) is a congenital anomaly syndrome caused by a variant in the CHD7 gene, which is necessary for fetal development. A deﬁciency in CHD7 function results in delayed fetal growth, audiovisual disturbances, and multi-system internal organ disease [2] . Several genetic studies have reported on families with children who had CHARGE syndrome-like features but normal CHD7 genes. For example, a pair of cousins from a single consanguineous family showed CHARGE syndrome-like features, including coloboma, renal malformation, restricted growth, and limb anomalies, but expressed a rare variant of the CDK9 gene, namely p.R225C [3] . In addition, three patients with CHARGE syndrome-like features from three different families were homozygous for this same CDK9 variant [4]. As part of the “Finding of Rare Disease Genes” (FORGE) Strategies for Gene Discovery initiative [5], we also previously reported on a patient who was compound heterozygous for two rare pathogenic CDK9 variants, namely p.A288T and R303C [6] . Thus, biallelic deﬁciency of CDK9 activity is now an established cause of a human multiple malformation syndrome that involves the eyes and features vision-threatening retinal dystrophy. I

FAQs

What is the key biological role of CDK9 described in the study?

CDK9 phosphorylates the C-terminal domain of RNA polymerase II to regulate transcription, forming a complex with cyclin T1 and influencing essential cellular responses.

How is the new CDK9 variant in the female patient identified?

Trio-based whole-exome sequencing identifies a de novo CDK9 allele, p.P321S, in addition to the maternal-origin p.A288T variant, resulting in compound heterozygous biallelic states.

What clinical difference distinguishes this patient from previously reported cases?

The female patient shows retinal dystrophy without a CHARGE-like malformation syndrome, unlike earlier reports where biallelic CDK9 variants were associated with CHARGE-like features.

Sep 29, 2026

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