The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects

Nagy, Amanda; Molay, Francine; Hargadon, Sarah; Brito Pires, Claudia; Grant, Natalie; De La Rosa Abreu, Lizbeth; Chen, Jin Yun; D’Souza, Precilla; Macnamara, Ellen; Tifft, Cynthia; Becker, Catherine; Melo De Gusmao, Claudio; Khurana, Vikram; Neumeyer, Ann M.; Eichler, Florian S.

doi:10.1186/s13023-024-03083-3

Orphanet Journal of Rare Diseases

Table 4 Comparison of genetic syndromes associated with autism spectrum disorder

From: The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects

Disorder	Gene	Inheritance	ASD	Regression	Seizures	GI issues	Sleep	Behavioral issues		Systemic involvement	Unique features
Disorder	Gene	Inheritance	ASD	Regression	Seizures	GI issues	Sleep	Self-injury	Repetitive behaviors	Systemic involvement	Unique features
TBL1XR1/Pierpont syndrome^a	TBL1XR1	AD	++	++	++	+++	+++	++	++	Renal and cardiac anomalies, anal malformation	Fetal fat pads, high forehead
Phelan McDermid syndrome	SHANK3	AD	++++	+++	++	++	++	++	++++	Renal and cardiac anomalies, hypothyroidism	Heat intolerance, fleshy hands, dysplastic toenails
Pitt-Hopkins syndrome	TCF4	AD	+++	–	++	++++	+	+++	++++	Paradoxical breathing pattern	Coarse facial features, overriding toes, fetal fat pads, peaked philtrum
Fragile X syndrome	FMR1	XLD	++	–	+	++	++	+++	+++	Macroorchidism cardiac anomalies	Long face, large/prominent ears, high-arched palate, and prominent jaw
Rett syndrome	MECP2	XLD	++/+++	++++	+++/+++	++	++	++/+++	++++	Paradoxical breathing pattern, vision, cardiac involvement	Stereotypic hand movement, loss of purposeful hand movement
Angelman syndrome	UBE3A	AD	+++	–	++++	++++	++++	++	+/++++	Vision	Happy disposition, frequent laughter, excitable personality

^aData taken from this survey
Frequency of features reported in surveys (TBL1XR1) or available literature (related disorders) is denoted as follows: + < 25%; ++ 25–49%; +++ 50 = 74%; ++++ > = 75%; –absent
Frequency of features associated with related genetic syndromes associated with autism spectrum disorder obtained from review of prior literature. Phelan McDermid Syndrome: Frank Y. The Neurological Manifestations of Phelan-McDermid Syndrome. Pediatr Neurol. 2021 Sep;122:59–64. Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, et al. Prospective investigation of autism and genotype–phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism. 2013 Jun 11;4:18. Pitt-Hopkins Syndrome: Goodspeed K, Newsom C, Morris MA, Powell C, Evans P, Golla S. Pitt-Hopkins Syndrome: A Review of Current Literature, Clinical Approach, and 23-Patient Case Series. J Child Neurol. 2018 Mar;33(3):233–44. Watkins A, Bissell S, Moss J, Oliver C, Clayton-Smith J, Haye L, et al. Behavioural and psychological characteristics in Pitt-Hopkins syndrome: a comparison with Angelman and Cornelia de Lange syndromes. J Neurodev Disord. 2019 Oct 5;11(1):24. Fragile X Syndrome: Oakes A, Thurman AJ, McDuffie A, Bullard LM, Hagerman RJ, Abbeduto L. Characterising repetitive behaviours in young boys with fragile X syndrome. J Intellect Disabil Res. 2016;60(1):54–67. Ciaccio C, Fontana L, Milani D, Tabano S, Miozzo M, Esposito S. Fragile X syndrome: a review of clinical and molecular diagnoses. Ital J Pediatr. 2017 Dec;43(1):39. Arron K, Oliver C, Moss J, Berg K, Burbidge C. The prevalence and phenomenology of self-injurious and aggressive behaviour in genetic syndromes. J Intellect Disabil Res. 2011;55(2):109–20. Moss J, Oliver C, Arron K, Burbidge C, Berg K. The Prevalence and Phenomenology of Repetitive Behavior in Genetic Syndromes. J Autism Dev Disord. 2009 Apr;39(4):572–88. Rett Syndrome: Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett Syndrome: A Genetic Update and Clinical Review Focusing on Comorbidities. ACS Chem Neurosci. 2018 Feb 21;9(2):167–76. Frullanti E, Papa FT, Grillo E, Clarke A, Ben-Zeev B, Pineda M, et al. Analysis of the Phenotypes in the Rett Networked Database. Int J Genomics. 2019 Mar 27;2019:6,956,934. Wulffaert J, Van Berckelaer-Onnes IA, Scholte EM. Autistic disorder symptoms in Rett syndrome. Autism. 2009 Nov 1;13(6):567–81. Cianfaglione R, Clarke A, Kerr M, Hastings RP, Oliver C, Moss J, et al. A national survey of Rett syndrome: behavioural characteristics. J Neurodev Disord. 2015 Mar 4;7(1):11. Angelman Syndrome: Bird LM. Angelman syndrome: review of clinical and molecular aspects. Appl Clin Genet. 2014 May 16;7:93–104. Glassman LW, Grocott OR, Kunz PA, Larson AM, Zella G, Ganguli K, et al. Prevalence of gastrointestinal symptoms in Angelman syndrome. Am J Med Genet A. 2017;173(10):2703–9. Larson AM, Shinnick JE, Shaaya EA, Thiele EA, Thibert RL. Angelman syndrome in adulthood. Am J Med Genet A. 2015 Feb;167(2):331–44

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