Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 3

A number sign (#) is used with this entry because of evidence that immunodeficiency-centromeric instability-facial anomalies syndrome-3 (ICF3) is caused by homozygous mutation in the CDCA7 gene (609937) on chromosome 2q31.

Description

Immunodeficiency-centromeric instability-facial anomalies syndrome-3 is an autosomal recessive disorder characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable (summary by Thijssen et al., 2015).

For a discussion of genetic heterogeneity of immunodeficiency-centromeric instability-facial anomalies syndrome, see ICF1 (242860).

Clinical Features

Thijssen et al. (2015) reported 5 patients from 4 unrelated families with an immunodeficiency syndrome characterized by recurrent upper respiratory infections and associated with hypo- or agammaglobulinemia with normal B cells. Cytogenetic studies showed abnormalities of chromosomes 1, 9, and 16, and hypomethylation of alpha-satellite DNA and pericentromeric satellite type II. One of the patients (family A) had previously been reported by Kloeckener-Gruissem et al. (2005) (as patient 2) and Braegger et al. (1991). This patient was born of consanguineous Turkish parents and had ischiadic hypoplasia, renal dysgenesis, polydactyly, and severe hypogammaglobulinemia with normal T-cell function. Other features included intrauterine growth retardation, microcephaly, psychomotor retardation, conductive hearing loss, craniofacial anomalies including flat face, hypertelorism, epicanthic folds, strabismus, short nose, and low-set ears, hypospadias, and cryptorchidism. Kloeckener-Gruissem et al. (2005) found that this patient later developed scoliosis, tapetoretinal degeneration, mental handicap, and suspected bilateral focal cortical heterotopy. Cytogenetic and Southern blot analysis showed that the patient had hypomethylation and centromeric instability of chromosomes 1 and 16, but did not have mutations in the DNMT3B gene (602900) or in genes encoding the DNMT3B-interacting proteins SUMO1 (601912) and UBC9 (UBE2I; 601661). Thijssen et al. (2015) noted that this patient died at 26 years of age. Of the other 4 patients reported by Thijssen et al. (2015), all had recurrent infections, 3 had facial anomalies, and 3 had gastrointestinal problems; only 1 had delayed psychomotor development. Two families were of Turkish origin and 2 were of French origin; 3 families were confirmed consanguineous.

Inheritance

The transmission pattern of ICF3 in the family reported by Thijssen et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 4 unrelated families with ICF3, Thijssen et al. (2015) identified 4 different homozygous missense mutations in the CDCA7 gene (609937.0001-609937.0004). The mutations were found by a combination of homozygosity mapping and whole-exome sequencing. Segregation of the mutations was confirmed in 1 family only. All the mutations occurred at residues in the conserved C-terminal zinc finger domain, but functional studies of the variants were not performed. Knockdown of the CDCA7 gene in mouse embryonic fibroblasts resulted in decreased CpG methylation at centromeric repeats.