Connexion

GENATLAS PHENOTYPE

last update : 30-11-2017

Symbol	ICF
Location	20q11.21
Name	Immunodeficiency, Centromeric instability, and Facial anomalies syndrome
Corresponding gene	DNMT3B
Main clinical features	facial dysmorphism with epicanthic folds, hypertelorism, flat nasal bridge and low set ears hypo or agammaglobulinemia in almost all patients severe infections in infancy, chronic gastrointestinal problems and failure to thrive may shorten life expectancy, mental retardation haematological malignancies reported in two patients centromere instability associated with the formation of complex multibranched chromosomes implicating chr 1, 16 and 9, mild mental retardation
Genetic determination	autosomal recessive
Function/system disorder	defense and immunity
	mental retardation
Type	chromosomal instability syndrome

Gene product

Name

DNA methyltransferase 3B

Mechanism(s)

Gene mutation	Chromosome rearrangement	Effect	Comments

various types			missense, alternative splicing, frameshift, in the catalytic domain, affecting the capacity to be stimulated by DNMT3L
	other		constitutive hypomethylation of 1qh and 9qh heterochromatin and very unusual multibranched chromosomes, not causal for the disease
nonsense		truncated protein	located at the N-terminus

Remark(s)

DNMT3B hypomorphic germline mutations are responsible for 2/3 of ICF cases; satellite DNA hypomethylation does no prevent HP1 proteins from associating with heterochromatin

S270P mutation affects DNMT3B functions via specific, non-covalent interaction with SUMO1 (PMID: 18762900))

In ICF cells, constitutive heterochromatin is hypomethylated and decondensed, metaphase chromosomes undergo rearrangements, and DNA replication is also altered in ICF cells (PMID: 22378288))