X-linked intellectual disability (Cantagrel type) in girl: clinical case from practice

X-linked mental retardation, Cantagrel type ((MIM #300912; ORPHA:85277) is characterised by marked neonatal hypotonia, severely delayed developmental milestones, gastroesophageal reflux, stereotypic movements of the hands, esotropia and infantile autism. The article describes the case of mutation in the KIAA2022 gene in a 5-year-old girl with epilepsy, psychomotor, speech and intellectual development delay, behavioral disorders and autistic characters. Previously unknown heterozygous mutation in KIAA2022 gene , 3 exon (p.Asp451fs) was detected by targeted sequencing. Mutation was validated by the Sanger sequencing. The mutation was not found in parents of the child. Skewed X-inactivation was not detected in the study of CAG-repeat, AR gene, 1 exon in the proband. Mutations in the KIAA2022 gene can cause epileptic encephalopathy and intellectual disability in both boys and girls. It is important for genetic testing, medical management and genetic counseling.

ген KIAA2022, X-сцепленная умственная отсталость, задержка психомоторного развития, нарушение речи, эпилепсия, таргетное экзомное секвенирование, KIAA2022 gene, X-linked intellectual disability, psychomotor development delay, speech disorder, epilepsy, targeted sequencing

1. Ropers H.H. and Hamel B.C. X-linked mental retardation. Nat. Rev.Genet. 2005;6:46-57.

2. Vandeweyer G. and Kooy R.F. Balanced translocations in mental retardation. Hum. Genet. 2009;126:133-147.

3. Koolen D.A., Pfundt R., de Leeuw N. et al. Genomic microarrays in mental retardation: a practical workflow for diagnostic applications. Hum. Mutat.2009;30:283-292.

4. Hu H., Wrogemann K., Kalscheuer V. et al. Mutation screening in 86 known X-linked mental retardation genes by droplet-based multiplex PCR and massive parallel sequencing. Hugo J.2009;3:41-49.

5. Cantagrel V., Lossi A., Boulanger S. et al. Disruption of a new X linked gene highly expressed in brain in a family with two mentally retarded males. J Med Genet.2004;41:736-742.

6. Van Maldergem L., Hou Q., Kalscheuer V. et al. Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth. Hum Mol Genet.2013;22:3306-3314.

7. Kuroda Y., Ohashi I., Naruto T. et al. Delineation of the KIAA2022 mutation phenotype: two patients with X-linked intellectual disability and distinctive features. Am J Med Genet Part A. 2015;167A:1349-1353.

8. Soden S., Saunders C., Willig L. et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014;6:265ra168.

9. Charzewska A., Rzonca S., Janeczko M. et al. A duplication of the whole KIAA2022 gene validates the gene role in the pathogenesis of intellectual disability and autism. Clin Genet. 2015;88:297-299.

10. Magome T., Hattori T., Taniguchi M. et al. XLMR protein related to neurite extension (Xpn/KIAA2022) regulates cell-cell and cell-matrix adhesion and migration. Neurochem Int. 2013;63:561-569.

11. Moysеs-Oliveira M, Guilherme RS, Meloni VA et al. X-linked intellectual disability related genes disrupted by balanced X-autosome translocations. Am J Med Genet Part B Neuropsychiatr Genet. 2015;168:669-677.

12. Athanasakis E, Licastro D, Faletra F. et al. Next generation sequencing in nonsyndromic intellectual disability: From a negative molecular karyotype to a possible causative mutation detection. Am J Med Genet Part A. 2014;164:170-176.

13. Farach LS, Northrup H. KIAA2022 nonsense mutation in a symptomatic female. Am J Med Genet Part A. 2016;170:703-706.

14. Lange I, Helbig K, Weckhuysen S. et al. De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy. J Med Genet. 2016;0:1-9.

15. Dobyns WB. The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked. Acta Paediatrica.2006;95:11-15.

16. Dobyns WB, Filauro A, Tomson BN. et al. Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet Part A.2004;129:136-143.

17. Van den Veyver IB. Skewed X inactivation in X-linked disorders. Semin Reproductive Med.2001;19:183-191.

18. Cantagrel V, Haddad M-R, Ciofi P. et al. Villard L. Spatiotemporal expression in mouse brain of Kiaa2022, a gene disrupted in two patients with severe mental retardation. Gene Expr Patterns.2009;9:423-429.