Format

Send to

Choose Destination
Genome Med. 2019 Feb 28;11(1):12. doi: 10.1186/s13073-019-0623-0.

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.

Author information

1
Baylor Genetics, Houston, TX, 77021, USA.
2
Present address: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
3
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
5
Nottingham Genetics Service, Nottingham City Hospital, Nottingham, UK.
6
Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, 78207, USA.
7
North West Thames Regional Genetics Service, 759 Northwick Park Hospital, London, UK.
8
Dell Children's Medical Group, Austin, TX, 78723, USA.
9
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital; and Department of Pediatrics, College of Medicine, Ohio State University, Columbus, OH, 43205, USA.
10
Department of Pediatrics, College of Medicine & Health Sciences, United Arab University, Al Ain, UAE.
11
Department of Pediatrics, Tawam Hospital, Al-Ain, UAE.
12
Department of Pediatrics, Section of Genetics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
13
Present address: Mayo Clinic Florida, Department of Clinical Genomics, Jacksonville, FL, 32224, USA.
14
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.
15
Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
16
The Hebrew University of Jerusalem, Jerusalem, Israel.
17
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, 91120, Jerusalem, Israel.
18
Department of Pediatrics, Texas Children's Hospital, Houston, TX, 77030, USA.
19
Department of Pediatrics, University of Hawaii, Honolulu, HI, 96826, USA.
20
Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.
21
Department of Neurology, Boston Children's Hospital, Boston, MA, 0211, USA.
22
Gene DX, Gaithersburg, MD, 20877, USA.
23
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners; and Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
24
East Anglia Regional Genetics Service, Addenbrooke's Hospital, Cambridge, UK.
25
All-Wales Medical Genetics Service, University Hospital of Wales, Cardiff, UK.
26
South East of Scotland Clinical Genetic Service, Western General Hospital, Edinburgh, UK.
27
North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.
28
South East Thames Regional Genetics Service, Guy's Hospital, London, UK.
29
Oxford Regional Genetics Service, Oxford University Hospitals, Oxford, UK.
30
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
31
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
32
Baylor Genetics, Houston, TX, 77021, USA. pengfeil@bcm.edu.
33
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. pengfeil@bcm.edu.

Abstract

BACKGROUND:

Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).

METHODS:

Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.

RESULTS:

We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

CONCLUSIONS:

TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

KEYWORDS:

22q13; Deletions; Haploinsufficiency; Loss-of-function variants; Neurodevelopmental disorders; Smith–Magenis syndrome; TCF20

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center