Current clinical evidence does not support a link between TBL1XR1 and Rett syndrome: Description of one patient with Rett features and a novel mutation in TBL1XR1, and a review of TBL1XR1 phenotypes

Abstract

Funding informationBlue Bird Circle, Houston Mutations in MECP2 are causative for Rett syndrome (RTT, OMIM 312750) in 95-97% of typical cases (Amir et al., 1999; Neul et al., 2008). In order to diagnose typical Rett syndrome, a patient must have undergone developmental regression after developing neurotypically in the first 6-18 months. Additional obligatory features are loss of acquired language, loss of purposeful hand skills, gait abnormalities (dyspraxia), and Rett-typical hand stereotypies such as hand-washing or hand-wringing (Neul et al., 2010). A diagnosis of atypical RTT is given if an individual presents with a period of regression followed by stabilization, at least 2 out of the 4 main criteria mentioned above, and at least 5 out of 11 supportive criteria (see Table 1 for RTT diagnostic criteria) (Neul et al., 2010).We present a 7-year-old female patient born at 39 weeks by emergent C-section due to rupture of membranes. Maternal age at time of birth was 30 years and paternal age was 27 years. There was no consanguinity. The patient has an older full sister (age 10) who is healthy and has developed normally. At birth, our patient weighed 3,402 g (69%ile) and measured 50.8 cm (82%ile) in length. Apgar scores at birth were both nine at 1 and 5 min. Immediate postnatal course was uneventful and she left the hospital at 4 days of life. The mother soon noticed a poor suck when breastfeeding and the patient was noted to have global neonatal hypotonia. For that reason, the patient has been receiving physiotherapy since infancy. She rolled over at 11 months and started walking at 23 months of age. At around 2 years she spoke five words and was also able to communicate using five to six gestures.Stereotypic hand movements in the form of tapping and clapping started when she was 2 years old, but she never developed handwringing or hand-washing stereotypies. By the age of 2.5 years the patient had acquired around 50 words, which were subsequently reduced to 6 words in a regression phase that lasted from the ages of 3 to 4.5 years. During this period, the patient became more withdrawn and grew more irritable. She also did not sleep through the night and often cried inconsolably. The mother also reports that her daughter previously had a pincer grasp, which regressed to a raking grip. Postregression the patient uses 5 words and communicates mostly with a PRC (Prentke Romich Company) communication device with which she reportedly expresses about 70 words. She maintains some purposeful hand use as she can hold a cup, uses utensils to feed herself, and communicates by pointing or touching the PRC device. Her hand use is apraxic. The patient can walk, climb stairs, and run. However, her gait is broad-based and she is clumsy. The patient has bruxism and high pain tolerance. She has infrequent breath-holding episodes, of the type that

Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort

“…The comparison showed that for ‘confirmed’ genes classified by the DECIPHER, only three genes, KMT2E , TBL1XR and TRIP12 , were not covered by the CES. These three genes were all rarely reported in previous studies, which should have little influence on the diagnosis of DD patients with behavioural troubles in this study 34–37. Additionally, we used ‘behavioural abnormalities’ as the search term and extracted a list containing 99 genes from the OMIM database.…”

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

“…Surface plasmon resonance assays show that MeCP2-TBLR1 (the direct binding subunit of the NCoR complex) interaction is relatively weak (K D 9.5 ± 0.5 µM), which could be due to a lack of physiological context in vitro, or it could indicate transient binding (Kruusvee et al, 2017). Evidence for NCoR mutations specifically causing Rett syndrome is lacking (Sakaguchi et al, 2018;Zaghlula et al, 2018). Instead, they can cause intellectual disabilities, rather than RTT, per se, similar to misregulation of other MeCP2-associated processes such as mRNA splicing or miRNA biogenesis, suggesting comparable importance of MeCP2's differing roles (Young et al, 2005;Ha and Kim, 2014).…”

TBL1XR1 associated intellectual disability, a new missense variant with dysmorphic features plus autism: Expanding the phenotypic spectrum

“…These two variants lie in the inner side of the ringshaped protein, formed by the eight WD40 domains, suggesting a similar pathogenic mechanism. There are other several patients with reported pathogenic SNVs in TBL1XR1 [1][2][3][4][5][6][7][8] showing different neurological phenotypes (ID, autism, epilepsy, schizophrenia, Rett features) but in only a few of them dysmorphic features are reported, some of these findings are present in Pierpont syndrome, 4,5 but not others 3,8 (Table 1).…”

“…Pathogenic mutations in TBL1XR1 gene were first described in 2012 1,2 in two patients with autism spectrum disorders (ASD). After that, single nucleotide pathogenic variants (SNVs) have been reported in several cases: a girl without dysmorphic features that developed West syndrome at 5 months of age and later was diagnosed with autism with Rett-like features 3 ; 6 patients, all with global developmental delay and no dysmorphic features, three of them with autism, diagnosed in the Deciphering Developmental Disorders (DDD) study 4 ; a young man with intellectual disability (ID), autism and dysmorphic features 5 ; a patient with sporadic schizophrenia 6 ; a 7-year-old girl with Rett features and no dysmorphic findings 7 ; and a 7-year-old boy with autism and facial dysmorphism. 8 In 2016, Heinen et al 9 reported the same SNV pathogenic variant, p.(Tyr446Cys), in TBL1XR1 gene in six patients clinically diagnosed with Pierpont syndrome.…”