Parenti–Migno neurodevelopmental disorder: a case associated with a new variant in the CHD5 gene

   Parenti–Migno neurodevelopmental disorder is a rare syndromal form of intellectual disability in children, associated with the CHD5 gene, the prevalence of which is not established. Currently, 16 patients with this pathology have been described. CHD5 belongs to the conservative family of chromatin remodeler proteins, is part of the histone deacetylase NuRD complex, and is crucial for the early differentiation of neurons in the central nervous system and acts as a tumor suppressor. Recently, thanks to the application of whole-exome sequencing, the association of this gene with Parenti–Migno neurodevelopmental disorder was first described in patients with developmental delay, psycho-neurological disturbances, facial phenotype features, and skull pathology. We present a unique case of the disease associated with a new variant p.Arg1521Thr in the CHD5 gene, in a girl with intellectual and neurological impairments, craniofacial dysmorphism, as well as previously undescribed symptoms such as cleft lip and palate, hydrocephalus, and renal pathology. The cause of the disease was determined through whole-genome sequencing, which highlights the value of this method in the diagnosis of undifferentiated forms of intellectual disabilities.

1. Parenti I., Lehalle D., Nava C., Torti E., Leitão E., Person R. et al. Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy. Hum Genet 2021; 140(7): 1109–1120. DOI: 10.1007/s00439–021–02283–2

2. Woodage T., Basrai M.A., Baxevanis A.D., Hieter P., Collins F.S. Characterization of the CHD family of proteins. Proc Natl Acad Sci USA 1997; 94(21): 11472–11477. DOI: 10.1073/pnas.94.21.11472

3. Thompson P.M., Gotoh T., Kok M., White P.S., Brodeur G.M. CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system. Oncogene 2003; 22(7): 1002–1011. DOI: 10.1038/sj.onc.1206211

4. Pier son T.M., Otero M.G., Grand K., Choi A., Graham J.M. Jr, Young J.I., Mackay J.P. The NuRD complex and macrocephaly associated neurodevelopmental disorders. Am J Med Genet C Semin Med Genet 2019; 181(4): 548–556. DOI: 10.1002/ajmg.c.31752

5. Shrestha P., Jaganathan A., Huilgol D., Ballon C., Hwangbo Y., Mills A.A. Chd5 Regulates the Transcription Factor Six3 to Promote Neuronal Differentiation. Stem Cells 2023; 41(3): 242–251. DOI: 10.1093/stmcls/sxad002

6. Bagchi A., Papazoglu C., Wu Y., Capurso D., Brodt M., Francis D. et al. CHD5 is a tumor suppressor at human 1p36. Cell 2007; 128(3): 459–475. DOI: 10.1016/j.cell.2006.11.052

7. Kolla V., Zhuang T., Higashi M., Naraparaju K., Brodeur G.M. Role of CHD5 in human cancers: 10 years later. Cancer Res 2014; 74(3): 652–658. DOI: 10.1158/0008–5472.CAN-13–3056

8. Shimada S., Shimojima K., Okamoto N., Sangu N., Hirasawa K., Matsuo M. et al. Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications. Brain Dev 2015; 37(5): 515–526. DOI: 10.1016/j.braindev.2014.08.002

9. Jacquin C., Landais E., Poirsier C., Afenjar A., Akhavi A., Bednarek N. et al. 1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients. Am J Med Genet A 2023; 191(2): 445–458. DOI: 10.1002/ajmg.a.63041

10. Heilstedt H.A, Ballif B.C., Howard L.A., Kashork C.D., Shaffer L.G. 1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients. Am J Med Genet A 2023; 191(2): 445–458. DOI: 10.1002/ajmg.a.63041

11. Battaglia A., Hoyme H.E., Dallapiccola B., Zackai E., Hudgins L., McDonald-McGinn D. et al. Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation [published correction appears in Pediatrics. 2008 May;121(5):1081. Braley, Lisa L [corrected to Brailey, Lisa L]]. Pediatrics 2008; 121(2): 404–410. DOI: 10.1542/peds.2007–0929

12. Bishop B., Ho K.K., Tyler K., Smith A., Bonilla S., Leung Y.F., Ogas J. The chromatin remodeler chd5 is necessary for proper head development during embryogenesis of Danio rerio. Biochim Biophys Acta 2015; 1849(8): 1040–1050. DOI: 10.1016/j.bbagrm.2015.06.006

13. Nagamani S.C., Erez A., Probst F.J., Bader P., Evans P., Baker L.A. et al. Small genomic rearrangements involving FMR1 support the importance of its gene dosage for normal neurocognitive function. Neurogenetics 2012; 13(4): 333–339. DOI: 10.1007/s10048–012–0340-y