IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

Abstract

Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

Keywords

IL1RAPL1 - electrical status epilepticus in sleep - continuous spike-waves during sleep - nonsyndromic X-linked ID

Note

This study was approved by the Institutional Review Board of the Children's Hospital of Philadelphia on November 6, 2015 (IRB protocol number: 15–012226). Informed consent was obtained from the patient's legal guardians. Informed consent for participation in this study was provided by the patient's parents.

Publication History

Received: 12 January 2021

Accepted: 09 June 2021

Article published online:
13 July 2021

• References

• 1 Carrié A, Jun L, Bienvenu T. et al. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nat Genet 1999; 23 (01) 25-31
• 2 Pavlowsky A, Gianfelice A, Pallotto M. et al. A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Curr Biol 2010; 20 (02) 103-115
• 3 Bahi N, Friocourt G, Carrié A. et al. IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with neuronal calcium sensor-1 and regulates exocytosis. Hum Mol Genet 2003; 12 (12) 1415-1425
• 4 Gambino F, Kneib M, Pavlowsky A. et al. IL1RAPL1 controls inhibitory networks during cerebellar development in mice. Eur J Neurosci 2009; 30 (08) 1476-1486
• 5 Montani C, Gritti L, Beretta S, Verpelli C, Sala C. The synaptic and neuronal functions of the X-linked intellectual disability protein interleukin-1 receptor accessory protein like 1 (IL1RAPL1). Dev Neurobiol 2019; 79 (01) 85-95
• 6 Piton A, Michaud JL, Peng H. et al; S2D team. Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum Mol Genet 2008; 17 (24) 3965-3974
• 7 Behnecke A, Hinderhofer K, Bartsch O. et al. Intragenic deletions of IL1RAPL1: report of two cases and review of the literature. Am J Med Genet Part A 2011; 155A [phone]
• 8 Achermann JC, Vilain EJ. NR0B1-Related Adrenal Hypoplasia Congenita. Seattle, WA: University of Washington; (1993–2021):
• 9 Koh JW, Kang SY, Kim GH, Yoo HW, Yu J. Central precocious puberty in a patient with X-linked adrenal hypoplasia congenita and Xp21 contiguous gene deletion syndrome. Ann Pediatr Endocrinol Metab 2013; 18 (02) 90-94
• 10 Korkut S, Baştuğ O, Raygada M. et al. Complex glycerol kinase deficiency and adrenocortical insufficiency in two neonates. J Clin Res Pediatr Endocrinol 2016; 8 (04) 468-471
• 11 Sasaki R, Inamo Y, Saitoh K, Hasegawa T, Kinoshita E, Ogata T. Mental retardation in a boy with congenital adrenal hypoplasia: a clue to contiguous gene syndrome involving DAX1 and IL1RAPL. Endocr J 2003; 50 (03) 303-307
• 12 Wheway JM, Yau SC, Nihalani V. et al. A complex deletion-inversion-deletion event results in a chimeric IL1RAPL1-dystrophin transcript and a contiguous gene deletion syndrome. [2] J Med Genet 2003; 40 (02) 127-131
• 13 Proposal for revised classification of epilepsies and epileptic syndromes: commission on classification and terminology of the international league against epilepsy. Epilepsia 1989; 30 (04) 389-399
• 14 Sánchez Fernández I, Loddenkemper T, Peters JM, Kothare SV. Electrical status epilepticus in sleep: clinical presentation and pathophysiology. Pediatr Neurol 2012; 47 (06) 390-410
• 15 Kessi M, Peng J, Yang L. et al. Genetic etiologies of the electrical status epilepticus during slow wave sleep: systematic review. BMC Genet 2018; 19 (01) 40
• 16 Lesca G, Rudolf G, Labalme A. et al. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism. Epilepsia 2012; 53 (09) 1526-1538
• 17 Laumonnier F, Ronce N, Hamel BCJ. et al. Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet 2002; 71 (06) 1450-1455
• 18 Moysés-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 (08) 669-677
• 19 Xiol C, Vidal S, Pascual-Alonso A. et al; Rett Working Group. X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients. Sci Rep 2019; 9 (01) 11983
• 20 Ponzoni L, Sala C, Verpelli C, Sala M, Braida D. Different attentional dysfunctions in eEF2K^-/-, IL1RAPL1^-/- and SHANK3Δ11^-/- mice. Genes Brain Behav 2019; 18 (05) e12563
• 21 Park H, Choi Y, Jung H. et al. Splice-dependent trans-synaptic PTPδ-IL1RAPL1 interaction regulates synapse formation and non-REM sleep. EMBO J 2020; 39 (11) e104150
• 22 Leprêtre F, Delannoy V, Froguel P, Vasseur F, Montpellier C. Dissection of an inverted X(p21.3q27.1) chromosome associated with mental retardation. Cytogenet Genome Res 2003; 101 (02) 124-129
• 23 Tabolacci E, Pomponi MG, Pietrobono R, Terracciano A, Chiurazzi P, Neri G. A truncating mutation in the IL1RAPL1 gene is responsible for X-linked mental retardation in the MRX21 family. Am J Med Genet A 2006; 140 (05) 482-487
• 24 Kozák L, Chiurazzi P, Genuardi M, Pomponi MG, Zollino M, Neri G. Mapping of a gene for non-specific X linked mental retardation: evidence for linkage to chromosomal region Xp21.1-Xp22.3. J Med Genet 1993; 30 (10) 866-869
• 25 Nawara M, Klapecki J, Borg K. et al. Novel mutation of IL1RAPL1 gene in a nonspecific X-linked mental retardation (MRX) family. Am J Med Genet Part A 2008; 146A (24) 3167-3172
• 26 Bhat SS, Ladd S, Grass F. et al. Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism. Clin Genet 2008; 73 (01) 94-96
• 27 Honda S, Hayashi S, Imoto I. et al. Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis. J Hum Genet 2010; 55 (09) 590-599
• 28 Whibley AC, Plagnol V, Tarpey PS. et al. Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability. Am J Hum Genet 2010; 87 (02) 173-188
• 29 Boone PM, Bacino CA, Shaw CA. et al. Detection of clinically relevant exonic copy-number changes by array CGH. Hum Mutat 2010; 31 (12) 1326-1342
• 30 Mikhail FM, Lose EJ, Robin NH. et al. Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. Am J Med Genet Part A 2011; 155A (10) 2386-2396
• 31 Franek KJ, Butler J, Johnson J. et al. Deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X-linked intellectual disability associated with behavioral problems and mild dysmorphism. Am J Med Genet A 2011; 155A [phone]
• 32 Isrie M, Froyen G, Devriendt K. et al. Sporadic male patients with intellectual disability: contribution of X-chromosome copy number variants. Eur J Med Genet 2012; 55 (11) 577-585
• 33 Youngs EL, Henkhaus R, Hellings JA, Butler MG. IL1RAPL1 gene deletion as a cause of X-linked intellectual disability and dysmorphic features. Eur J Med Genet 2012; 55 (01) 32-36
• 34 Barone C, Bianca S, Luciano D, Di Benedetto D, Vinci M, Fichera M. Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems. Am J Med Genet Part A 2013; 161A [phone]
• 35 Dinopoulos A, Stefanou MI, Attilakos A, Tsirouda M, Papaevangelou V. A case of startle epilepsy associated with IL1RAPL1 gene deletion. Pediatr Neurol 2014; 51 (02) 271-274
• 36 Utine GE, Haliloğlu G, Volkan-Salancı B. et al. Etiological yield of SNP microarrays in idiopathic intellectual disability. Eur J Paediatr Neurol 2014; 18 (03) 327-337
• 37 Mignon-Ravix C, Cacciagli P, Choucair N. et al. Intragenic rearrangements in X-linked intellectual deficiency: Results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes. Am J Med Genet A 2014; 164A [phone]
• 38 Pinto D, Delaby E, Merico D. et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet 2014; 94 (05) 677-694
• 39 Redin C, Gérard B, Lauer J. et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet 2014; 51 (11) 724-736
• 40 Tucker T, Zahir FR, Griffith M. et al. Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes. Eur J Hum Genet 2014; 22 (06) 792-800
• 41 Ramos-Brossier M, Montani C, Lebrun N. et al. Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis. Hum Mol Genet 2015; 24 (04) 1106-1118
• 42 Morgan A, Gandin I, Belcaro C. et al. Target sequencing approach intended to discover new mutations in non-syndromic intellectual disability. Mutat Res 2015; 781: 32-36
• 43 Hu H, Haas SA, Chelly J. et al. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry 2016; 21 (01) 133-148
• 44 Laino L, Bottillo I, Piedimonte C. et al. Clinical and molecular characterization of a boy with intellectual disability, facial dysmorphism, minor digital anomalies and a complex IL1RAPL1 intragenic rearrangement. Eur J Paediatr Neurol 2016; 20 (06) 971-976
• 45 Whitehead MT, Helman G, Gropman AL. MR imaging findings in Xp21.2 duplication syndrome. J Radiol Case Rep 2016; 10 (05) 9-14
• 46 Chatron N, Thibault L, Lespinasse J. et al. Genetic counselling pitfall: co-occurrence of an 11.8-Mb Xp22 duplication and an Xp21.2 duplication disrupting IL1RAPL1 . Mol Syndromol 2017; 8 (06) 325-330
• 47 Du X, Gao X, Liu X. et al. Genetic diagnostic evaluation of trio-based whole exome sequencing among children with diagnosed or suspected autism spectrum disorder. Front Genet 2018; 9: 594
• 48 Fernández-Marmiesse A, Roca I, Díaz-Flores F. et al. Rare variants in 48 genes account for 42% of cases of epilepsy with or without neurodevelopmental delay in 246 pediatric patients. Front Neurosci 2019; 13: 1135