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Intellectual disability v9.157 TSPAN7 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: TSPAN7.
Intellectual disability v9.97 TSPAN7 Eleanor Williams 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
Intellectual disability v9.96 TSPAN7 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype term accessed on 22nd September 2025
Intellectual disability v9.96 TSPAN7 Eleanor Williams 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,
Intellectual disability v9.95 TSPAN7 Eleanor Williams Publications for gene: TSPAN7 were set to
Intellectual disability v9.94 TSPAN7 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: TSPAN7.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: 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.

Other variants reported as pathogenic 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.; to: 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.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: 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 our criteria for Intellectual Disability testing: IQ<50, global developmental delay, childhood onset. 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.; to: 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.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: 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 our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

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.

Other variants reported as pathogenic 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.; to: 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.

Other variants reported as pathogenic 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.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: 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 our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

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.

Other variants reported as pathogenic 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.; to: 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 our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

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.

Other variants reported as pathogenic 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.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska commented on gene: TSPAN7: 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 our criteria for Intellectual Disability testing: IQ<50, global developmental delay, childhood onset. 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.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: 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 our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

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.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 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) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: 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/browser - 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.; to: 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 our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

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.

Other variants reported as pathogenic 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.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska edited their review of gene: TSPAN7: Changed rating: AMBER
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: 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 our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

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.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 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) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: 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/browser - 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.; to: 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 our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

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.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 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) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: 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/browser - 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.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska reviewed gene: TSPAN7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10655063, 12376945, 14735593, 12070254, 22511893, 26290131; Phenotypes: Intellectual developmental disorder, X-linked 58, OMIM:300210, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v2.468 TSPAN7 Louise Daugherty Source Victorian Clinical Genetics Services was added to TSPAN7.
Intellectual disability TSPAN7 BRIDGE consortium edited their review of TSPAN7
Intellectual disability TSPAN7 BRIDGE consortium edited their review of TSPAN7
Intellectual disability TSPAN7 BRIDGE consortium reviewed TSPAN7