See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on allelic variants detected in this gene.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants detected may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Connell et al [2009] suggest that a pathogenic variant is detected in 75% of those clearly affected and with a positive family history and in 68% of those with typical Milroy features but without a family history.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Gene-targeted deletion/duplication analysis has not identified any deletions or duplications of FLT4 that are causative of Milroy disease. The molecular mechanism of disease causation is likely dominant negative, such that deletions/duplications of FLT4 are not likely to cause Milroy disease (see Genetically Related Disorders). Data are derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017].

No other loci have been identified, but reports suggest that Milroy disease is genetically heterogeneous [Holberg et al 2001, Evans et al 2003]. Even when the individual has a clear clinical diagnosis, an FLT4 pathogenic variant is found in up to 75% of affected individuals, suggesting that other genes may be involved [Connell et al 2009]. Rare cases may be caused by pathogenic variants in VEGFC [Gordon et al 2013a, Balboa-Beltran et al 2014, Fastré et al 2018, Nadarajah et al 2018].