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In their letter, Huynh et al. [1] report three patients carrying an interstitial 2q12.3q13 microdeletion and suggest that this copy number variation would predispose to developmental delay and behavioral disorders.
Since original publication [1], patient 2 underwent whole exome sequencing (WES) given the clinical evolution towards severe psychomotor delay associated with progressive postnatal microcephaly. Moreover, a novel cerebral MRI showed white matter abnormalities suggesting a delayed myelination.
WES revealed a homozygous MED23 missense variant: Chr6(GRCh37):g.131908944G > A c.3982C > T p.(Arg1328Cys). This variant has been reported with a significant low frequency at a heterozygous state (0.00001596) in the gnomAD v2.1.1 database and was predicted to be pathogenic by bioinformatic models with a phred CADD v1.4 score = 32. Furthermore, this variant was reported as pathogenic in Clinvar (RCV000987783.1) for a patient presenting with intellectual disability.
Variants in this gene have been described as responsible for non-syndromic intellectual disability with or without epilepsy [2,3,4,5,6]. Some of the described patients presented with cerebral MRI anomalies such as delayed or decreased myelination [2, 3, 6]. One patient presented with progressive postnatal microcephaly [5]. Clinical features of our patient were consistent with the reported phenotype, so we concluded that our patient’s phenotype was related to MED23.
These additional data raised doubts about the pathogenicity of the 2q12.3q13 microdeletion. Furthermore, among the 7/16 cases reported by Huynh et al. [1] for which the inheritance data was available, we would like to raise concern about this microdeletion being inherited in 6/7 cases including 2 cases from an asymptomatic parent. Indeed, the only patient with a de novo 2q12.3q13 microdeletion is our patient who also carries a likely pathogenic variant in MED23.
Considering these data, we propose for the 2q12.3q13 microdeletion to be considered as a variant of unknown significance, until new data is available.
References
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Jury, J., Nizon, M., Cogné, B. et al. Response to a letter to the editor. Neurogenetics 24, 219 (2023). https://doi.org/10.1007/s10048-023-00721-z
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DOI: https://doi.org/10.1007/s10048-023-00721-z