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Intellectual disability

Gene: TSPAN7

Green List (high evidence)
TSPAN7 (tetraspanin 7)
EnsemblGeneIds (GRCh38): ENSG00000156298
EnsemblGeneIds (GRCh37): ENSG00000156298
OMIM: 300096, Gene2Phenotype
TSPAN7 is in 3 panels

5 reviews

Eleanor Williams (Genomics England Curator)

Comment on phenotypes: OMIM phenotype term accessed on 22nd September 2025
Created: 22 Sep 2025, 2:55 p.m. | Last Modified: 22 Sep 2025, 2:55 p.m.
Panel Version: 9.96
Created: 22 Sep 2025, 2:55 p.m.
Last Modified: 22 Sep 2025, 2:55 p.m.
Panel version: 9.96

Ida Ertmanska (Genomics England Curator)

I don't know

Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.
Created: 22 Sep 2025, 1:50 p.m. | Last Modified: 22 Sep 2025, 2:09 p.m.
Panel Version: 9.94
There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Supporting evidence - variants in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Created: 22 Sep 2025, 1:45 p.m. | Last Modified: 22 Sep 2025, 2:16 p.m.
Panel Version: 9.94

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Intellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0001071

Publications

Created: 22 Sep 2025, 1:45 p.m.
Last Modified: 22 Sep 2025, 2:16 p.m.
Panel version: 9.94

Caroline Wright (Sanger)

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
MENTAL RETARDATION X-LINKED TYPE 58

Publications

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_gilissen_2014_known . Main mutation mechanism : Loss of function
Created: 27 Jul 2017, 8:48 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; find_uk10k; gilissen_2014_known; sfari_20150206; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_green_20160217; neuro_20160418_strict; Loss of function. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 1:37 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

Created: 2 Aug 2017, 11:21 p.m.

Panel version: 1.354

Lu Raymond (university of cambridge )

Green List (high evidence)

Created: 23 Feb 2016, 10:59 a.m.

Panel version: 0.306

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Victorian Clinical Genetics Services
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Emory Genetics Laboratory
Phenotypes
  • ntellectual developmental disorder, X-linked 58, OMIM:300210
  • intellectual disability, X-linked 58, MONDO:0010266
Tags
Q3_25_expert_review Q3_25_demote_amber
OMIM
300096
Clinvar variants
Variants in TSPAN7
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Oct 2025, Gel status: 3

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_25_expert_review tag was added to gene: TSPAN7.

22 Sep 2025, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: TSPAN7 were changed from ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0010266 X-linked 58, to ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, X-linked 58, MONDO:0010266

22 Sep 2025, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: TSPAN7 were changed from Mental retardation, X-linked 58, 300210; MENTAL RETARDATION X-LINKED TYPE 58 to ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0010266 X-linked 58,

22 Sep 2025, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: TSPAN7 were set to

22 Sep 2025, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_25_demote_amber tag was added to gene: TSPAN7.

29 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to TSPAN7.

12 Mar 2018, Gel status: 3

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

TSPAN7 was added to Intellectual disabilitypanel. Source: Expert Review Green Model of inheritance for gene TSPAN7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females

24 Jun 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene TSPAN7 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females

24 Jun 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

TSPAN7 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

TSPAN7 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen