Paediatric pseudo-obstruction syndrome

Gene: FLNA

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

Comment on classification of this gene: The rating for this gene should be GREEN as this gene has been implicated in intestinal pseudo-obstruction, as identified from five unrelated families.

Four patients from family 1 reported with intestinal pseudo-obstruction in PMID:20871226 had diffuse abnormal layering of small intestinal smooth muscle (DAL). At least five males were affected in this family and they were all maternally-related. Both the mother and sister of patient 1 have normal intestinal motility and cranial magnetic resonance imaging, but the sister had a PDA and bifid uvula. Patient 5 from a second family was also reported with variant in FLNA gene (c.7021C>T; p.Gln2341Ter) and the parents also gave birth to a healthy female. Bot these cases suggest biallelic mode of inheritance in females.

2-bp deletion in exon 2 of the FLNA gene was found in the male proband and his second cousin and the variant was present in heterozygous state in the carrier females of the family (PMID:17357080). Similarly, a 4-bp deletion in exon 40 was identified in PMID:26059841, which results in translation of a mutant FLNA missing an internal region of 41 amino acids.

In another family, three males and four females were identified with a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). This variant causes classical X-linked periventricular nodular heterotopia (XL-PNH) in females and an unusual multi-organ phenotype in males (PMID:23873601).

This gene is associated with relevant phenotypes in both OMIM and Gene2Phenotype.

Created: 20 Dec 2022, 10:22 p.m. | Last Modified: 20 Dec 2022, 10:43 p.m.

Panel Version: 0.36

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

Phenotypes
Congenital short bowel syndrome, OMIM:300048; Intestinal pseudoobstruction, neuronal, OMIM:300048

Publications

• 17357080
• 20871226
• 23873601
• 26059841
• 31848803
• 33729000

Review submitted on behalf of Dr. Anna Rybak and Dr. Osvaldo Borreli, Great Ormond Street Hospital for Children NHS Foundation Trust. Gene group: Myopathic PIPO/MMIHS. Protein function: Filamin A, Encodes large cytoskeletal proteins.

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

Panel Version: 0.2

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Cytoskeletal abnormalities and potentially disrupts enteric-neuron structure and function. Seizures and progressive abdominal distension and obstruction

Publications

• 33729000
• 31848803