Paediatric pseudo-obstruction syndrome

Gene: L1CAM

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, biallelic mutations in females' following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 7:44 a.m. | Last Modified: 1 Feb 2023, 7:44 a.m.

Panel Version: 0.216

Added a 'monogenic-polygenic' tag based on patient in PMID:22344793 who carried both L1CAM and RET variants.

Created: 21 Dec 2022, 11:30 a.m. | Last Modified: 21 Dec 2022, 11:30 a.m.

Panel Version: 0.58

Comment on rating: The rating of this gene should be GREEN, as this gene has been implicated in sufficient (>3) unrelated cases of L1CAM variants in patients with concurrent X-linked hydrocephalus and Hirschsprung disease.

Detailed review:
In a child with features of X-linked hydrocephalus (307000) who also had Hirschsprung disease and cleft palate, Okamoto et al. (1997, PMID:9279760) identified a 2-bp deletion of exon 18 in the L1CAM gene, resulting in a frameshift and premature termination. XLH and HSCR may be independent events in this patient, but the authors suggested that L1CAM may contribute to both phenotypes.

Parisi et al. (2002, PMID:11857550) describe a male infant who had severe hydrocephalus (MIM:307000) and Hirschsrpung disease. The patient had a 2254G-A mutation in L1CAM (V752M). Parisi et al. stated that this patient represented the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation.

Fernández et al., 2012 (PMID:22344793) describe a new patient with concurrent X-linked hydrocephalus and Hirschsprung disease together with a G698R hemizygous mutation in L1CAM. The patient also carried the RET mutation c.73 + 9277T > C.

Jackson et al., 2009 (PMID:19641926) describe a case of a patient with concurrent X-linked hydrocephalus and Hirschsprung disease. The patient was hemizygous for a R558X hemizygous variation in the L1CAM gene.

In 2 brothers with hydrocephalus (MIM:307000) and Hirschsprung disease, Okamoto et al. (2004, PMID:15148591) identified a splice-site mutation in L1CAM. A third case had a nonsense variant in exon 22 (C2974T, Cln992Stop) and hydrocephalus alongside HSCR.

Created: 21 Dec 2022, 11:27 a.m. | Last Modified: 21 Dec 2022, 11:27 a.m.

Panel Version: 0.54

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

Phenotypes
Hydrocephalus with congenital idiopathic intestinal pseudoobstruction, OMIM:307000

Publications

• 28543993
• 20860806
• 22344793
• 11857550
• 15148591
• 19641926
• 9279760

Review submitted on behalf of Dr. Anna Rybak and Dr. Osvaldo Borreli, Great Ormond Street Hospital for Children NHS Foundation Trust. Gene group: Other primary PIPO with identified genetic mutations. Protein function: transmembrane glycoprotein involved in neurite outgrowth and neuronal migration.

Created: 20 Dec 2022, 3:32 p.m. | Last Modified: 20 Dec 2022, 3:32 p.m.

Panel Version: 0.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Defect in the differentiation of the interstitial cells of Cajal leading to progressive distension and intermittent episodes of obstruction

Publications

• 31848803