Early onset or syndromic epilepsy

Gene: SHROOM4

Green List (high evidence)

Comment on list classification: There are more than 3 unrelated individuals with hemizygous SHROOM4 variants (missense and non-canonical splice) and isolated epilepsy. Other cases have been reported with SHROOM4 variants and variable ID, congenital malformations, and CC agenesis - the mechanism of disease is not yet clear. Hence, SHROOM4 is tagged for promotion to Green with a request for expert review, due to confounding evidence of disease association. Addition of SHROOM4 to this panel would ensure inclusion on the R27 Paediatric disorders panel.

Created: 21 Apr 2026, 3:25 p.m. | Last Modified: 21 Apr 2026, 3:38 p.m.

Panel Version: 8.187

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: 35937050 Lee et al., 2022
Cohort of patients with infantile spasms. Sample IS06 - male; trio WGS detected a SHROOM4 NM_020717: c.269+4A>G hemizygous variant - classified as VUS by authors.

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).
Sources: Literature

Created: 21 Apr 2026, 3:19 p.m.

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

Phenotypes
epilepsy, MONDO:0005027

Publications

• 16249884
• 25167861
• 26740508
• 32565546
• 32728808
• 35663265
• 35937050
• 36379543
• 40905141