Ficolin 3 Deficiency

A number sign (#) is used with this entry because of evidence that ficolin-3 deficiency is caused by homozygous mutation in the FCN3 gene (604973) on chromosome 1p36.

Description

Individuals with ficolin-3 deficiency have highly variable manifestations and a variable age of symptom onset. Some patients may show increased susceptibility to infection in the perinatal or neonatal period, whereas others may show autoimmune features as adults. Ficolin-3, also known as H-ficolin, can activate the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by Munthe-Fog et al., 2009 and Michalski et al., 2015).

For a discussion of genetic heterogeneity of lectin complement activation pathway defects, see LCAPD1 (614372).

Clinical Features

Munthe-Fog et al. (2009) reported a patient with immunodeficiency and recurrent infections since childhood who had a complete ficolin-3 deficiency. Other features included brain abscesses and recurrent warts on the fingers. He had normal levels of lymphocytes, normal T-cell responses, and normal antibodies, but a selective deficient antibody response to pneumococcal polysaccharide vaccine. Laboratory studies showed impaired complement deposition when acetylated bovine serum albumin was used, indicating a defect in complement activation.

Schlapbach et al. (2011) reported 2 unrelated infants who were born prematurely and developed necrotizing enterocolitis associated with severe H-ficolin deficiency. One of the patients died at age 4 weeks; DNA was not available. The other patient recovered, but had repeated skin infections with Staphylococcus aureus. At age 4 years, he had no major infections. Schlapbach et al. (2011) postulated that the ficolin deficiency in these patients rendered them more susceptible to the disease. These patients were ascertained from a cohort of 32 infants with necrotizing enterocolitis who were assessed for components of the lectin pathway of complement activation. The surviving child was homozygous for the common truncating FCN3 polymorphism (604973.0001).

Michalski et al. (2012) reported a male infant born at 35 weeks' gestation who developed infection with Streptococcus agalactiae. Laboratory studies showed complete H-ficolin deficiency as well as low MBL (MBL2; 154545), undetectable MASP2 (605102), and low L-ficolin (FCN2; 601624). He had no severe infections during a 5-year follow-up, but he did have microcephaly, poor growth, and mental retardation. The patient was homozygous for the common FCN3 truncating polymorphism (604973.0001).

Michalski et al. (2015) reported 2 unrelated patients with ficolin-3 deficiency. One was a 50-year-old man with nephrotic syndrome due to membranous nephropathy. Immunosuppressive therapy resulted in reactivation of an Epstein-Barr virus infection that remitted after withdrawal of treatment. He had no other severe infections during his lifetime. The other patient was an 11-month-old boy who had pneumonia before surgery to repair a cardiac ventricular septal defect. He had no complications from the surgery, and no serious infections during the following months. Both patients were homozygous for the common FCN3 polymorphism (604973.0001) and had decreased or undetectable serum ficolin-3. The older patient had high MBL2 levels, whereas the infant had low MBL2 levels. Michalski et al. (2015) concluded that the consequences of FCN3 deficiency are not clear-cut, and suggested that it may act as a disease modifier.

Inheritance

The transmission pattern of complete FCN3 deficiency in the family reported by Schlapbach et al. (2011) was consistent with autosomal recessive inheritance. The parents, who were heterozygous for the mutation, had about a 50% decrease in serum FCN3 levels, indicating haploinsufficiency.

Molecular Genetics

In a man with immunodeficiency and recurrent infections associated with ficolin-3 deficiency, Munthe-Fog et al. (2009) identified homozygosity for a 1-bp deletion (1637delC; 604973.0001) in exon 5 of the FCN3 gene. The patient was born of Macedonian and Albanian parents, both of whom were unaffected and heterozygous for the variant. The allele frequency of the variant was 0.01 among a total of 1,282 patients with various immunodeficiencies; all were heterozygous for the variant except the index patient.

The 4 unrelated patients with complete FCN3 deficiency reported by Schlapbach et al. (2011), Michalski et al. (2012), and Michalski et al. (2015) were homozygous for the same c.1637delC mutation originally reported by Munthe-Fog et al. (2009).

Population Genetics

Michalski et al. (2012) evaluated serum H-ficolin levels in 613 neonates, and FNC3 genotypes in 529 neonates; all were of Polish descent. Genotype analysis revealed that 96% were homozygous wildtype, 3.8% were compound heterozygous, and 0.2% (1 infant) was homozygous for the variant allele. The protein was undetectable in the homozygous infant. Preterm delivery and low birthweight were significantly associated with low serum H-ficolin, but not with heterozygosity for the c.1637delC allele, even though the variant allele influenced the protein level. There was no association between heterozygosity for the allele and perinatal infections. Michalski et al. (2012) concluded that heterozygosity for the FCN3 variant does not seem to have major clinical importance.