<scp><i>TBL1XR1</i></scp> associated intellectual disability, a new missense variant with dysmorphic features plus autism: Expanding the phenotypic spectrum

Carrera, I. Arroyo; Fernández‐Burriel, Miguel; Lapunzina, Pablo; Tenorio, Jair; Navas, Verónica Deyanira García; Isidro, Elena Márquez

doi:10.1111/cge.13937

Cited by 10 publications

(9 citation statements)

References 20 publications

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“…KMT2A, MED13L, PHIP and SETD5 would not commonly be referred to as CdLS genes but the heterozygous LOF mutations identified in probands 3236, 3057, 4248 and 3036, respectively, are comparable to those previously reported in CdLS (10, 24). The remaining six probands (4021, 4482, 4383, 3046, 4353 & 3035) have variants in genes which have not been implicated in CdLS before but are known to be associated with non-syndromic ( NLGN3 (31), SET (32)) and/or syndromic ( EBF3 (33), NR2F1 (34), PUF60 (35), TBL1XR1 (36, 37)) intellectual disability, respectively (proven de novo in 4482 and 4353). We could not determine whether these variants represent false positive, contributary or fully explanatory molecular diagnoses for the CdLS-like phenotype in the probands.…”

Section: Resultsmentioning

confidence: 99%

Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome

Ansari

Halachev

Campos

et al. 2022

Preprint

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Aims This study assesses the diagnostic utility of whole genome sequence analysis in a well-characterised research cohort of individuals referred with a clinical suspicion of Cornelia de Lange syndrome (CdLS) in whom prior genetic testing had not identified a causative variant. Methods Short read, whole genome sequencing was performed in 195 individuals from 105 families, 108 of whom were affected. 100/108 of the affected individuals had prior relevant genetic testing with no pathogenic variant being identified. The study group comprised 42 trios (affected individuals with both unaffected parents), 61 singletons (unrelated affected individuals) and two families with more than one affected individual. Results 32/105 (30.5%) unrelated probands had likely causative coding region disrupting variants. 4 loci were identified in >1 proband; NIPBL (10), ANKRD11 (6), EP300 (3), EHMT1 (2). Single alleles were detected in the remaining genes (EBF3, KMT2A, MED13L, NLGN3, NR2F1, PHIP, PUF60, SET, SETD5, SMC1A, TBL1XR1). Possibly causative variants in non-coding regions of NIPBL were identified in four individuals. Single de novo variants were identified in five genes not previously reported to be associated with any developmental disorder: ARID3A, PIK3C3, MCM7, MIS18BP1 and WDR18. Conclusions Clustering of de novo non-coding variants implicate a single uORF and a small region in intron 21 in NIPBL regulation. Causative variants in genes encoding chromatin-associated proteins, with no defined influence on cohesin function, appear to result in CdLS-like clinical features.

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Section: Resultsmentioning

confidence: 99%

Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome

Ansari

Halachev

Campos

et al. 2022

Preprint

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“…On reverse phenotyping (reevaluation of the patient after the genetic report), we appreciated our patient to have features of PS 1 2 3 4 5 6 including distinct crescent moon-shaped eyes when the child smiled. Our patient however did not have HL and the classic deep palmar and plantar grooves described in other case reports of PS ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…1 2 3 4 5 6 A varied spectrum of variants has been described in TBL1XR1 , ranging from microdeletions to single-nucleotide variations (SNVs; missense, frameshift, and nonsense). 5 6 Variants in TBL1XR1 cause a pleiotropic spectrum of overlapping disorders, occurring in varying combinations of the following features: global developmental delay (GDD), nonsyndromic and syndromic intellectual disability (ID), neuropsychiatric and behavioral issues, seizures, facial dysmorphisms, tone abnormalities, and growth delays. 6 7 Among these, a recurrent, de novo, missense variant in TBL1XR1 has been described as being associated with a distinct syndrome called as Pierpont's syndrome (PS).…”

Section: Introductionmentioning

confidence: 99%

“…2 3 4 Later, three additional cases of PS, each associated with a variant other than p.Tyr446Cys were reported. 5 6 Analyzing the genotype and phenotype of 10 cases of PS (8 with p.Tyr446Cys and one each p.Tyr446His and p.Cys325Tyr), Quan et al postulated that the non-p.Tyr446Cys variant in TBL1XR1 is more commonly associated with neurobehavioral and autistic spectrum. 7 This thought was backed by another recent report (2021), describing the association of ASD features in PS and non-p.Tyr446Cys missense variant in TBL1XR1 , viz, p.Gly237Asp.…”

Section: Introductionmentioning

confidence: 99%

“…The transducin β-like-1 X-linked-receptor-1 gene ( TBL1XR1 ) encodes for the TBL1XR1 protein which plays a pivotal role in gene transcription. 1 2 3 4 5 6 A varied spectrum of variants has been described in TBL1XR1 , ranging from microdeletions to single-nucleotide variations (SNVs; missense, frameshift, and nonsense). 5 6 Variants in TBL1XR1 cause a pleiotropic spectrum of overlapping disorders, occurring in varying combinations of the following features: global developmental delay (GDD), nonsyndromic and syndromic intellectual disability (ID), neuropsychiatric and behavioral issues, seizures, facial dysmorphisms, tone abnormalities, and growth delays.…”

Section: Introductionmentioning

confidence: 99%

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

Bajaj¹,

Gadgil

Seenappa³

et al. 2022

Journal of Pediatric Neurology

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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.

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A novel de novo pathogenic variant in TBL1XR1 as a new proposed cause of Pierpont syndrome

Tamma

Streff

Murali

2023

American J of Med Genetics Pt A

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TBL1XR1, which encodes transducing β‐like 1 X‐linked receptor 1, is implicated in both Pierpont syndrome and intellectual developmental disorder, autosomal dominant‐41 (MRD‐41, OMIM #616944). While both conditions are autosomal dominant, variants associated with Pierpont syndrome are believed to behave in a dominant negative fashion, whereas those causing MRD‐41 result in haploinsufficiency. Here, we present a patient with a de novo novel variant in TBL1XR1 (c.977G > A,p.S326N) identified by trio exome sequencing. Though a different variant at this same residue has previously been associated with MRD‐41, our patient's presentation is suggestive of Pierpont syndrome. The patient's clinical phenotype, which includes short stature, developmental delay, dysmorphic craniofacial features, and plantar fat pads, more closely resembles that of known patients with Pierpont syndrome than MRD‐41. Furthermore, this missense variant is directly adjacent to one previously associated with Pierpont syndrome and exists in the same region as all variants associated with Pierpont, on the inner surface of a WD40 ring. We propose this variant is a newly identified cause of Pierpont syndrome.

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

Cited by 10 publications

References 20 publications

Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome

Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome

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

A novel de novo pathogenic variant in TBL1XR1 as a new proposed cause of Pierpont syndrome

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