Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 4

A number sign (#) is used with this entry because of evidence that immunodeficiency-centromeric instability-facial anomalies syndrome-4 (ICF4) is caused by homozygous or compound heterozygous mutation in the HELLS gene (603946) on chromosome 10q23.

Description

Immunodeficiency-centromeric instability-facial anomalies syndrome-4 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 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. All but 1 patient (a younger sib of another patient) had recurrent infections, all had facial anomalies, and 3 had delayed psychomotor development. The families were of various ethnic origins, including English, Japanese, French, and Italian; one family was confirmed to be consanguineous. One patient died at 1.2 years of age; 2 sibs underwent stem cell transplantation.

Inheritance

The transmission pattern of ICF4 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 ICF4, Thijssen et al. (2015) identified 6 homozygous or compound heterozygous mutations in the HELLS gene (603946.0001-603946.0006). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the families. Only 1 of the mutations was a missense mutation. Functional studies of the variants were not performed, but knockdown of the HELLS gene in mouse embryonic fibroblasts resulted in decreased CpG methylation at centromeric repeats, similar to that observed in patient cells.