Confirmation and Expansion of the Phenotype Associated with the Recurrent p.Val837Met Variant in TRPM3

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Abstract

Dyment et al. (2019) recently reported eight novel patients with intellectual disability and epilepsy associated with heterozygous de novo missense variants in TRPM3. We report a novel patient with the same recurrent de novo missense of TRPM3 found in seven of these eight cases, p.(Val837Met), providing an emphasis towards ocular and joints defects along with a non-mandatory epilepsy.

Section snippets

Report

The patient is a 5-year-old girl. She is the first child of unrelated French parents and was born at full term with normal measurements. She presented with bilateral hips and patellar dislocations necessitating multiple surgical interventions. She presented early with neurodevelopmental delay, intellectual disability (ID) and hypotonia, consistent with previous reports: she was able to sit at age 3 and a half and walked at 5, which is consistent with previous cases considering the repeated

Material & methods

Exome sequencing was performed by IntegraGen SA (Evry, France) with a standard protocol of library preparation, exome capture and sequencing based on Gnirke et al. (2009) (details available upon request) as follow: DNA fragments (150–200 bp) were obtained via sonication, exomes were enriched and captured using Twist Bioscience kits, and library preparation realized with kit NEBNext® Ultra kit (New England Biolabs®). DNA fragments were sequenced as 75bp pair-end runs on an Illumina HiSeq4000

Discussion

TRPM3 is a cation channel activated by heat and is highly expressed in nociceptor neurons (Vriens et al., 2011). The involvement of the Val837Met missense in the neurologic symptoms (ID, epilepsy) described in the patients does not fit well with the sole noxious somatosensory role of TRPM3, and suggests additional neurodevelopmental roles for TRPM3. Its expression in myelinating oligodendrocytes (Hoffmann et al., 2010) does not explain the symptoms as no systematic myelination defects has been

Conclusion

Our 5 years old patient is to date the only Val837Met case without epilepsy, suggesting a partial expressivity of the phenotypical spectrum, although it should be noted that the patient may have epilepsy at a later age, in the same way as individual 1 in Dyment et al. (2019) who was diagnosed with epilepsy at the age of 7.

Additionally, the presence of joint and ocular defects in this patient highlights those described in the previous cases and is probably part of the clinical signs of this new

Data availability statement

Data is available on request from the authors.

Editorial policies and ethical considerations

For the facial photographs of the patient, an informed written consent for publication has been obtained from the parents.

Declaration of competing interest

There are no conflicts of interest.

Acknowledgements

This work has not been supported by any fund. The authors gratefully thank the contribution and commitment of the patient and her parents.

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