Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Pediatrics
Published in: BMC Pediatrics 1/2021

Open Access 01-12-2021 | Disorders of Intellectual Development | Case report

Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report

Authors: Xin Xu, Fen Lu, Li Zhang, Hongying Li, Senjie Du, Jian Tang

Published in: BMC Pediatrics | Issue 1/2021

Login to get access

Abstract

Background

The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl−/H+ exchanger ClC-4 prominently expressed in brain.

Case presentation

We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools.

Conclusion

Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family.
Appendix
Available only for authorised users
Literature
1.
Hu H, Haas SA, Chelly J, Van Esch H, Raynaud M, de Brouwer AP, et al. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2016;21(1):133–48.CrossRef
2.
Palmer EE, Stuhlmann T, Weinert S, Haan E, Van Esch H, Holvoet M, et al. De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females. Mol Psychiatry. 2018;23(2):222–30.CrossRef
3.
Veeramah KR, Johnstone L, Karafet TM, Wolf D, Sprissler R, Salogiannis J, et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia. 2013;54(7):1270–81.CrossRef
4.
Scheel O, Zdebik AA, Lourdel S, Jentsch TJ. Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature. 2005;436(7049):424–7.CrossRef
5.
Jentsch TJ. Discovery of CLC transport proteins: cloning, structure, function and pathophysiology. J Physiol. 2015;593(18):4091–109.CrossRef
6.
Picollo A, Pusch M. Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature. 2005;436(7049):420–3.CrossRef
7.
Mohammad-Panah R, Harrison R, Dhani S, Ackerley C, Huan LJ, Wang Y, et al. The chloride channel ClC-4 contributes to endosomal acidification and trafficking. J Biol Chem. 2003;278(31):29267–77.CrossRef
8.
Suzuki T, Rai T, Hayama A, Sohara E, Suda S, Itoh T, et al. Intracellular localization of ClC chloride channels and their ability to form hetero-oligomers. J Cell Physiol. 2006;206(3):792–8.CrossRef
9.
Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, van Mierlo P, Braakman HMH, Smeets EE, et al. Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability. Epilepsia. 2019;60(1):155–64.CrossRef
10.
Fernández-Marmiesse A, Roca I, Díaz-Flores F, Cantarín V, Pérez-Poyato MS, Fontalba A, et al. Rare variants in 48 genes account for 42% of cases of epilepsy with or without neurodevelopmental delay in 246 pediatric patients. Front Neurosci. 2019;13:1135.CrossRef
11.
Kosmicki JA, Samocha KE, Howrigan DP, Sanders SJ, Slowikowski K, Lek M, et al. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017;49(4):504–10.CrossRef
12.
Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18(7):696–704.CrossRef
13.
Wang C, Han Y, Zhou J, Zheng B, Zhou W, Bao H, et al. Splicing characterization of CLCNKB variants in four patients with type III Bartter syndrome. Front Genet. 2020;11:81.CrossRef
14.
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
15.
de Brouwer AP, Yntema HG, Kleefstra T, Lugtenberg D, Oudakker AR, de Vries BB, et al. Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium. Hum Mutat. 2007;28(2):207–8.CrossRef
16.
van Bokhoven H. Genetic and epigenetic networks in intellectual disabilities. Annu Rev Genet. 2011;45:81–104.CrossRef
17.
Neri G, Schwartz CE, Lubs HA, Stevenson RE. X-linked intellectual disability update 2017. Am J Med Genet A. 2018;176(6):1375–88.CrossRef
18.
Feng L, Campbell EB, Hsiung Y, MacKinnon R. Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle. Science. 2010;330(6004):635–41.CrossRef
19.
Park E, Campbell EB, MacKinnon R. Structure of a CLC chloride ion channel by cryo-electron microscopy. Nature. 2017;541(7638):500–5.CrossRef
20.
Jentsch TJ, Pusch M. CLC chloride channels and transporters: structure, function, physiology, and disease. Physiol Rev. 2018;98(3):1493–590.CrossRef
21.
Hur J, Jeong HJ, Park J, Jeon S. Chloride channel 4 is required for nerve growth factor-induced TrkA signaling and neurite outgrowth in PC12 cells and cortical neurons. Neuroscience. 2013;253:389–97.CrossRef
Metadata
Title
Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report
Authors
Xin Xu
Fen Lu
Li Zhang
Hongying Li
Senjie Du
Jian Tang
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Pediatrics / Issue 1/2021
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-021-02860-4

Other articles of this Issue 1/2021

BMC Pediatrics 1/2021 Go to the issue

Research

Predictive value of early amplitude integrated electroencephalogram (aEEG) in sleep related problems in children with perinatal hypoxic-ischemia (HIE)

Research

Health services use by children identified as heterozygous hemoglobinopathy mutation carriers via newborn screening

Correction

Correction to: The effect of vitamin D and magnesium supplementation on the mental health status of attention-deficit hyperactive children: a randomized controlled trial

Study protocol

Motor-enriched learning for improving pre-reading and word recognition skills in preschool children aged 5–6 years – study protocol for the PLAYMORE randomized controlled trial

Research

Post-Ebola sequelae among Ebola child survivors in Sierra Leone

Research article

Clinical aspects for differential diagnosis of Kawasaki disease shock syndrome: a case control study