Novel De Novo TBL1XR1 Variant Causing PIERPONT Syndrome in an Indian Child: A Case Report and Genotype–Phenotype Review of Reported Patients

Abstract

The transducin β-like-1 X-linked-receptor-1 gene (TBL1XR1) encodes for the TBL1XR1 protein which is involved in transcription. Single-nucleotide variants (SNVs) in the TBL1XR1 gene have been reported to be associated with Pierpont's syndrome (PS) which exhibits numerous features including global developmental delay (GDD), intellectual disability (ID), varying neurobehavioral and psychiatric manifestations with/without autism spectrum disorder (ASD), abnormal fat distribution in the distal extremities, short stature (SS), head circumference abnormalities, hearing loss (HL), and facial dysmorphisms. Eight PS patients, having a de novo mutation resulting in p.Tyr446Cys, showed no manifestations of ASD. The three other PS patients, having mutations resulting in p.Tyr446His, p.Cys325Tyr and p.Gly237Asp, respectively, and without the p.Tyr446Cys alteration, were in addition associated with neurobehavioral abnormalities, including ASD, hyperactivity, and self-mutilation tendencies. Here, via trio whole exome sequencing, we describe a 12th PS patient, the first from the Indian subcontinent, reflecting a novel TBL1XR1 p.His348Arg alteration. The proband is a 4.5-year-old male having GDD, speech delay, facial dysmorphisms, abnormal digital fat pads, hypotonia, microcephaly, patent ductus arteriosus, and ASD features. Our report strengthens the hypothesis that TBL1XR1 variants coding for the TBL1XR1 protein other than p.Tyr446Cys might be more commonly associated with a neurobehavioral phenotype and autistic tendencies.

Keywords

next-generation sequencing - developmental delay disorders - autism - facial dysmorphism - genotype–phenotype correlation

Publication History

Received: 22 October 2021

Accepted: 22 February 2022

Article published online:
22 April 2022

• References

• 1 Pierpont ME, Stewart FJ, Gorlin RJ. Plantar lipomatosis, unusual facial phenotype and developmental delay: a new MCA/MR syndrome. Am J Med Genet 1998; 75 (01) 18-21
• 2 Heinen CA, Jongejan A, Watson PJ. et al. A specific mutation in TBL1XR1 causes Pierpont syndrome. J Med Genet 2016; 53 (05) 330-337
• 3 Kahlert AK, Weidensee S, Mackenroth L. et al. Pierpont syndrome: report of a new patient. Clin Dysmorphol 2017; 26 (04) 205-208
• 4 Slavotinek A, Pua H, Hodoglugil U. et al. Pierpont syndrome associated with the p.Tyr446Cys missense mutation in TBL1XR1. Eur J Med Genet 2017; 60 (10) 504-508
• 5 Lemattre C, Thevenon J, Duffourd Y. et al. TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation. Am J Med Genet A 2018; 176 (12) 2813-2818
• 6 Arroyo Carrera I, Fernández-Burriel M, Lapunzina P, Tenorio JA, García Navas VD, Márquez Isidro E. TBL1XR1 associated intellectual disability, a new missense variant with dysmorphic features plus autism: expanding the phenotypic spectrum. Clin Genet 2021; 99 (06) 812-817
• 7 Quan Y, Zhang Q, Chen M. et al. Genotype and phenotype correlations for TBL1XR1 in neurodevelopmental disorders. J Mol Neurosci 2020; 70 (12) 2085-2092
• 8 Centers for Disease Control and Prevention. . Autism spectrum disorder (ASD). Accessed December 3, 2021 at: https://www.cdc.gov/ncbddd/autism/hcp-screening.html#DiagnosticTools
• 9 Ventola P, Kleinman J, Pandey J. et al. Differentiating between autism spectrum disorders and other developmental disabilities in children who failed a screening instrument for ASD. J Autism Dev Disord 2007; 37 (03) 425-436
• 10 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 11 Campbell IM, Stewart JR, James RA. et al. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am J Hum Genet 2014; 95 (04) 345-359
• 12 Wei H, Mundade R, Lange KC, Lu T. Protein arginine methylation of non-histone proteins and its role in diseases. Cell Cycle 2014; 13 (01) 32-41
• 13 Blanc RS, Richard S. Arginine methylation: the coming of age. Mol Cell 2017; 65 (01) 8-24
• 14 Li L, Cao Y, Zhao F. et al. Validation and classification of atypical splicing variants associated with osteogenesis imperfecta. Front Genet 2019; 10: 979
• 15 Harteveld CL, Wijermans PW, van Delft P, Rasp E, Haak HL, Giordano PC. An alpha-thalassemia phenotype in a Dutch Hindustani, caused by a new point mutation that creates an alternative splice donor site in the first exon of the alpha2-globin gene. Hemoglobin 2004; 28 (03) 255-259
• 16 Baralle D, Baralle M. Splicing in action: assessing disease causing sequence changes. J Med Genet 2005; 42 (10) 737-748