Haploinsufficiency of the MYT1L gene causes intellectual disability frequently associated with behavioral disorder.

Abstract

To the Editor: We read with great interest the research article by De Rocker et al.1.De Rocker N. Vergult S. Koolen D. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity.1:CAS:528:DC%2BC2MXhtFOjt7vK10.1038/gim.2014.124Genet Med. 2015; 17: 460-466Google Scholar on the MYT1L gene and its role in intellectual disability (ID). Based on a series of 22 patients with different aberrations affecting this gene (deletions, mutations, and partial duplications), the authors describe the main clinical features associated with MYT1L haploinsufficiency as ID (22/22), speech delay (22/22), behavioral problems (19/22), and overweight (17/19). Apart from duplications, whose consequences may differ depending on their position, orientation, and other factors, only four of these patients present alterations affecting the MYT1L gene exclusively: two de novo point mutations and two de novo deletions. To contribute to this description, we would like to add one patient with a de novo intragenic deletion of MYT1L detected by comparative genomic hybridization array (arr(hg19) 2p25.3(1,843,177x2,1,844,493-1,983,593x1,2,000,941x2)dn). Our patient is the first daughter of an unrelated healthy couple; the girl was born at 40 weeks of gestation via a natural delivery and had a birth weight of 2,700 g (10th to 25th percentile) and neonatal hypotonia. At the time of examination (at 4.5 years of age), she weighed 18 kg (50th percentile), was 109 cm tall (90th percentile), and presented microcephaly. Neurologically, she presented psychomotor developmental delay; she walked at 31 months and spoke her first words at 18 months, she does not control her sphincters overnight, and she attends a special education center. Behavioral problems fit those of autistic spectrum disorders (aggressiveness toward others, avoidance of eye contact, echolalia, hand and oral stereotypies, and hyperactivity). She also shows convergent strabismus, myopia, recurrent otitis, and seizures. In relation to the association of MYT1L alteration with obesity proposed by De Rocker et al.,1.De Rocker N. Vergult S. Koolen D. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity.1:CAS:528:DC%2BC2MXhtFOjt7vK10.1038/gim.2014.124Genet Med. 2015; 17: 460-466Google Scholar our patient, with a weight in the normal range (50th percentile) in spite of a height in the 90th percentile (body mass index of 15.5 kg/m2), does not fit this criterion. Although overweight in patients with MYT1L haploinsufficiency was previously described as an early-onset feature,2.Doco-Fenzy M. Leroy C. Schneider A. Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes.1:CAS:528:DC%2BC3sXhs1Clt7rP10.1038/ejhg.2013.189Eur J Hum Genet. 2014; 22: 471-479Google Scholar we cannot reject the possibility that our patient will develop obesity in late childhood, as occurs in other patients.1.De Rocker N. Vergult S. Koolen D. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity.1:CAS:528:DC%2BC2MXhtFOjt7vK10.1038/gim.2014.124Genet Med. 2015; 17: 460-466Google Scholar On the other hand, taking into account the World Health Organization definition of overweight and obesity based on both weight and body mass index,3.World Health Organization. Obesity and overweight. Fact sheet 311. http://www.who.int/mediacentre/factsheets/fs311/en/ updated January 2015.Google Scholar it is remarkable that of the four patients with alteration affecting exclusively MYT1L who were described by De Rocker et al.,1.De Rocker N. Vergult S. Koolen D. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity.1:CAS:528:DC%2BC2MXhtFOjt7vK10.1038/gim.2014.124Genet Med. 2015; 17: 460-466Google Scholar only patient 10, with a body mass index > 30 kg/m2, strictly meets these criteria. Conversely, behavioral problems in our patient are strikingly similar to those reported by De Rocker et al,1.De Rocker N. Vergult S. Koolen D. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity.1:CAS:528:DC%2BC2MXhtFOjt7vK10.1038/gim.2014.124Genet Med. 2015; 17: 460-466Google Scholar including hyperactivity, aggressiveness toward others, avoidance of eye contact, echolalia, and hand and oral stereotypies. It is also of interest that, in addition to the two DECIPHER database–identified patients mentioned in the article (nos. 314 and 141), a third patient (255731) with a 0.47-Mb deletion affecting exclusively MYT1L has ID and autism as the only clinical descriptors. More patients would be needed to better characterize the resulting phenotype, but, given the clinical similarities between patients with deletion or point mutation of the MYT1L gene, it is becoming clear that haploinsufficiency of this gene causes ID frequently associated with behavioral disorders. The authors declare no conflict of interest. This study was supported by grants PI08/0648 and PI11/00389 (Fondo de Investigaciones Sanitarias, Ministerio de Ciencia e Innovación), AP-155/09 (Consellería de Sanitat), FEDER (Fondo Europeo de Desarrollo Regional), and Fundación Ramón Areces. S.M. was supported by an IIS La Fe/Fundación Bancaja fellowship. The authors are grateful for the cooperation of the patients and their families.