Top

BMC Neurology

Published in:

Open Access 01-12-2022 | Case report

A female case with novel KDM5C heterozygous variation presenting with Claes-Jensen type-like phonotype

Authors: Ruiyun Shen, Yanyang Li, Aiming Liang, Shijie Li, Chenlu Yang, Hongmei Huang

Published in: BMC Neurology | Issue 1/2022

Abstract

Background

Lysine(K)-specific demethylase 5C (KDM5C) dysfunction causes X-linked syndromic intellectual developmental disorder Claes-Jensen type in male patients. The clinical presentations of female individuals with heterozygous KDM5C variations vary widely and are only now beginning to be characterized in detail.

Case presentation

Herein, we identified a novel de novo heterozygous nonsense variation of KDM5C (c.3533C > A, p.S1178X) in a sporadic 4-year-old Chinese girl, who presented with Claes-Jensen type-like phenotypes, such as moderate developmental delay, serious expressive language delay, short stature, microcephaly, and typical facial particularities. Moreover, X-chromosome inactivation (XCI) analysis showed no significant skewed X-inactivation.

Conclusion

The report expands the genotype of KDM5C variation in female patients, delineates the phenotype of affected females in this well-known X-linked disorder, and also reinforces the necessity to consider this X-linked gene, KDM5C, in sporadic female patients.

Carmignac V, Nambot S, Lehalle D, Callier P, Moortgat S, Benoit V, et al. Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature. Clin Genet. 2020;98(1):43–55.CrossRef

Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, et al. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell. 2007;128(6):1077–88.CrossRef

Jensen LR, Amende M, Gurok U, Moser B, Gimmel V, Tzschach A, et al. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am J Hum Genet. 2005;76(2):227–36.CrossRef

Claes S, Devriendt K, Van Goethem G, Roelen L, Meireleire J, Raeymaekers P, et al. Novel syndromic form of X-linked complicated spastic paraplegia. Am J Med Genet. 2000;94(1):1–4.CrossRef

Goncalves TF, Goncalves AP, Fintelman Rodrigues N, dos Santos JM, Pimentel MM, Santos-Reboucas CB. KDM5C mutational screening among males with intellectual disability suggestive of X-Linked inheritance and review of the literature. Eur J Med Genet. 2014;57(4):138–44.CrossRef

Fieremans N, Van Esch H, de Ravel T, Van Driessche J, Belet S, Bauters M, et al. Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features. Eur J Med Genet. 2015;58(5):324–7.CrossRef

Hatch HAM, O’Neil MH, Marion RW, Secombe J, Shulman LH. Caregiver-reported characteristics of children diagnosed with pathogenic variants in KDM5C. Am J Med Genet A. 2021;185(10):2951–8.CrossRef

McMichael G, Bainbridge MN, Haan E, Corbett M, Gardner A, Thompson S, et al. Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy. Mol Psychiatry. 2015;20(2):176–82.CrossRef

Lippa NC, Barua S, Aggarwal V, Pereira E, Bain JM. A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report. BMC Neurol. 2021;21(1):358.CrossRef

10.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.CrossRef

11.

Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992;51(6):1229–39.

12.

Lambert JM, Ashi MO, Srour N, Delpy L, Sauliere J. Mechanisms and regulation of nonsense-mediated mRNA decay and nonsense-associated altered splicing in lymphocytes. Int J Mol Sci. 2020;21(4):1335.CrossRef

13.

Popp MW, Maquat LE. Leveraging rules of nonsense-mediated mRNA decay for genome engineering and personalized medicine. Cell. 2016;165(6):1319–22.CrossRef

14.

Johansson C, Velupillai S, Tumber A, Szykowska A, Hookway ES, Nowak RP, et al. Structural analysis of human KDM5B guides histone demethylase inhibitor development. Nat Chem Biol. 2016;12(7):539–45.CrossRef

15.

Rujirabanjerd S, Nelson J, Tarpey PS, Hackett A, Edkins S, Raymond FL, et al. Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation. Eur J Hum Genet. 2010;18(3):330–5.CrossRef

16.

Brookes E, Laurent B, Ounap K, Carroll R, Moeschler JB, Field M, et al. Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity. Hum Mol Genet. 2015;24(10):2861–72.CrossRef

17.

Abidi FE, Holloway L, Moore CA, Weaver DD, Simensen RJ, Stevenson RE, et al. Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia. J Med Genet. 2008;45(12):787–93.CrossRef

18.

Santos-Reboucas CB, Fintelman-Rodrigues N, Jensen LR, Kuss AW, Ribeiro MG, Campos M Jr, et al. A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay. Neurosci Lett. 2011;498(1):67–71.CrossRef

19.

Vallianatos CN, Raines B, Porter RS, Bonefas KM, Wu MC, Garay PM, et al. Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation. Commun Biol. 2020;3(1):278.CrossRef

20.

Poeta L, Padula A, Lioi MB, van Bokhoven H, Miano MG. Analysis of a set of KDM5C regulatory genes mutated in neurodevelopmental disorders identifies temporal coexpression brain signatures. Genes (Basel). 2021;12(7):1088.CrossRef

21.

Vallianatos CN, Farrehi C, Friez MJ, Burmeister M, Keegan CE, Iwase S. Altered gene-regulatory function of KDM5C by a novel mutation associated with autism and intellectual disability. Front Mol Neurosci. 2018;11:104.CrossRef

22.

Scandaglia M, Lopez-Atalaya JP, Medrano-Fernandez A, Lopez-Cascales MT, Del Blanco B, Lipinski M, et al. Loss of Kdm5c causes spurious transcription and prevents the fine-tuning of activity-regulated enhancers in neurons. Cell Rep. 2017;21(1):47–59.CrossRef

23.

Wu PM, Yu WH, Chiang CW, Wu CY, Chen JS, Tu YF. Novel variations in the KDM5C gene causing X-linked intellectual disability. Neurol Genet. 2022;8(1):e646.CrossRef

24.

Kawano-Matsuda F, Maeda T, Kaname T, Yanagi K, Ihara K. X-linked mental retardation and severe short stature with a novel mutation of the KDM5C gene. Clin Pediatr Endocrinol. 2021;30(1):61–4.CrossRef

25.

Hatch HAM, Secombe J. Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes-Jensen syndrome. FEBS J. 2021. https://doi.org/10.1111/febs.16204.

26.

Iwase S, Brookes E, Agarwal S, Badeaux AI, Ito H, Vallianatos CN, et al. A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation. Cell Rep. 2016;14(5):1000–9.CrossRef

27.

Xu J, Burgoyne PS, Arnold AP. Sex differences in sex chromosome gene expression in mouse brain. Hum Mol Genet. 2002;11(12):1409–19.CrossRef

28.

Belalcazar HM, Hendricks EL, Zamurrad S, Liebl FLW, Secombe J. The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction. Cell Rep. 2021;34(7):108753.CrossRef

29.

Sun YX, Zhang YX, Zhang D, Xu CM, Chen SC, Zhang JY, et al. XCI-escaping gene KDM5C contributes to ovarian development via downregulating miR-320a. Hum Genet. 2017;136(2):227–39.CrossRef

30.

Guerra JVS, Oliveira-Santos J, Oliveira DF, Leal GF, Oliveira JRM, Costa SS, et al. DNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation. Eur J Med Genet. 2020;63(3):103737.CrossRef

31.

Schenkel LC, Aref-Eshghi E, Skinner C, Ainsworth P, Lin H, Pare G, et al. Peripheral blood epi-signature of Claes-Jensen syndrome enables sensitive and specific identification of patients and healthy carriers with pathogenic mutations in KDM5C. Clin Epigenetics. 2018;10:21.CrossRef

Title: A female case with novel KDM5C heterozygous variation presenting with Claes-Jensen type-like phonotype
Authors: Ruiyun Shen
Yanyang Li
Aiming Liang
Shijie Li
Chenlu Yang
Hongmei Huang
Publication date: 01-12-2022
Publisher: BioMed Central
Published in: BMC Neurology / Issue 1/2022
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-022-03023-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A female case with novel KDM5C heterozygous variation presenting with Claes-Jensen type-like phonotype

Abstract

Background

Case presentation

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Case presentation

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2022

Real-world disease-modifying therapy pathways from administrative claims data in patients with multiple sclerosis

3D slicer-based calculation of hematoma irregularity index for predicting hematoma expansion in intracerebral hemorrhage

Anti-dipeptidyl-peptidase-like protein 6 encephalitis with pure cerebellar ataxia: a case report

Self-reported sleep characteristics associated with dementia among rural-dwelling Chinese older adults: a population-based study

Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome - a prospective cohort study

Study protocol of Branch Atheromatous Disease-related stroke (BAD-study): a multicenter prospective cohort study