Cerebral Palsy

Gene: FLNA

Red List (low evidence)

Duplication: ClinGen has assessed this gene as 'no evidence' for triplosensitivity.

I can't see inheritance information provided for the FLNA variants in the Chinese cohort paper. One of the variants reported p.P1291L is reported as pathogenic in OMIM in 2007 but has subsequently been submitted as likely benign/benign by multiple clinical laboratories in ClinVar. The second variant, p.V591I is similarly classified as VOUS/LB by clinical laboratories.

This leaves a single canonical splice site variant reported in the EJHG paper, which also lacks further supporting evidence.

Created: 30 May 2023, 6:58 a.m. | Last Modified: 30 May 2023, 6:58 a.m.

Panel Version: 1.40

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
Heterotopia, periventricular, 1, MIM#300049

Green List (high evidence)

In a large Chinese cohort study two male patients with hemizygous FLNA missense mutations and spastic hemiplegic CP were identified. One additional patient in a cohort study of 52 patients with CP investigated for causative CNVs. This patient harbored a pathogenic maternally inherited triplication on Xq28 including FLNA. No information about the patient's gender is given.
One other cohort study (PMID 29706646) of patients with cortical malformations, which can be associated with CP overlapping features, also revealed one female patient with maternally inherited heterozygous FLNA mutation and ataxia. The mother had the same neuroradiologic features but did not show any symptoms.
Sources: Literature

Created: 29 May 2023, 6:14 a.m.

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
Cardiac valvular dysplasia MIM#314400; Congenital short bowel syndrome MIM#300048; Frontometaphyseal dysplasia MIM#305620; Heterotopia, periventricular MIM#300049; Intestinal pseudoobstruction MIM#300048; Melnick-Needles syndrome MIM#309350; Otopalatodigital syndrome I MIM#311300; Otopalatodigital syndrome II MIM# 304120; Terminal osseous dysplasia MIM#300244

Publications

• 29706646
• 34077496
• 25817843