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Intellectual disability

Gene: SHROOM4

Amber List (moderate evidence)
SHROOM4 (shroom family member 4)
EnsemblGeneIds (GRCh38): ENSG00000158352
EnsemblGeneIds (GRCh37): ENSG00000158352
OMIM: 300579, Gene2Phenotype
SHROOM4 is in 3 panels

5 reviews

Ida Ertmanska (Genomics England Curator)

I don't know

Comment on list classification: The association between SHROOM4 and Intellectual disability has been disputed by ClinGen in 2021, mostly due to reported SHROOM4 variants being too common in gnomAD. Subsequent publications reported SHROOM4 variants as causal in six individuals with epilepsy without ID, two unrelated cases with syndromic congenital malformations without ID / DD, and two fetal cases with CC agenesis. There are 3 unrelated cases reported with ID / DD and insertion or deletion affecting SHROOM4, in addition to other genes. As the effect of disrupting other genes cannot be decoupled, these cases are not taken into account for gene-disease association. Due to limited and conflicting evidence linking SHROOM4 to Intellectual disability, this gene can only be rated Amber for now.
Created: 21 Apr 2026, 2:58 p.m. | Last Modified: 21 Apr 2026, 2:58 p.m.
Panel Version: 9.384
The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36209347 Peduto et al., 2022
Report of a 2yo male with SHROOM4 c.4153C>T, p.Arg1385*, which is also present in an unaffected grandfather. The authors question pathogenicity of SHROOM4 LoF variants (missense GoF still seen as potentially disease causing).

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Created: 21 Apr 2026, 2:04 p.m. | Last Modified: 21 Apr 2026, 3:10 p.m.
Panel Version: 9.386

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

Phenotypes
neurodevelopmental disorder, MONDO:0700092

Publications

Created: 21 Apr 2026, 2:04 p.m.
Last Modified: 21 Apr 2026, 3:10 p.m.
Panel version: 9.384

Arianna Tucci (Genomics England Curator)

Comment when marking as ready: Marked as amber as not enough evidence to mark as green
Created: 5 Jan 2018, 12:07 p.m.
Created: 5 Jan 2018, 12:07 p.m.

Panel version: Imported from Intellectual disability update Dec 2017 panel version 0.128

Louise Daugherty (Genomics England Curator)

I don't know

One large 4 generation family and 1 unrelated patient have been reported to date with Stocco dos Santos X-linked mental retardation syndrome PMID:16249884 and 26740508.
Created: 18 Dec 2017, 3:39 p.m.

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

Phenotypes
Stocco dos Santos X-linked mental retardation syndrome, 300434; Intellectual disability

Publications

Created: 18 Dec 2017, 3:39 p.m.

Panel version: Imported from Intellectual disability update Dec 2017 panel version 0.40

Caroline Wright (Sanger)

Red List (low evidence)

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

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

Panel version: 0

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:12 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
  • Radboud University Medical Center, Nijmegen
  • Emory Genetics Laboratory
Phenotypes
  • neurodevelopmental disorder, MONDO:0700092
  • X-linked intellectual disability, Stocco dos Santos type, MONDO:0010325
Tags
disputed
OMIM
300579
Clinvar variants
Variants in SHROOM4
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

21 Apr 2026, Gel status: 2

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: SHROOM4 were changed from Stocco dos Santos X-linked mental retardation syndrome, 300434; Intellectual disability to neurodevelopmental disorder, MONDO:0700092; X-linked intellectual disability, Stocco dos Santos type, MONDO:0010325

21 Apr 2026, Gel status: 2

Set publications

Ida Ertmanska (Genomics England Curator)

Publications for gene: SHROOM4 were set to 12673656; 16249884; 26740508; 20613765

21 Apr 2026, Gel status: 2

Added Tag

Ida Ertmanska (Genomics England Curator)

Tag disputed tag was added to gene: SHROOM4.

29 Sep 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to SHROOM4.

16 May 2018, Gel status: 2

Clear Sources

Louise Daugherty (Genomics England Curator)

SHROOM4 Source: Expert Review Red was removed from gene: SHROOM4

12 Mar 2018, Gel status: 2

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.

5 Jan 2018, Gel status: 2

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene SHROOM4 was set to ['12673656', '16249884', '26740508', '20613765']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

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)

SHROOM4 was added to Intellectual disabilitypanel. Source: Expert Review Red Model of inheritance for gene SHROOM4 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 SHROOM4 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)

SHROOM4 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)

SHROOM4 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen