Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities

Lara Kamal, Sarah B. Pierce, Christina Canavati, Amal Abu Rayyan, Tamara Jaraysa, Orit Lobel, Suhair Lolas, Barbara M. Norquist, Grace Rabie, Fouad Zahdeh, Ephrat Levy-Lahad, Mary Claire King, Moien N. Kanaan

Research output: Contribution to journalArticlepeer-review


Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is BRIP1, in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in BRIP1, very few have been functionally characterized. We evaluated the functional consequence of BRIP1 p.R848H (c.2543G > A), which was homozygous in two cousins with low birth weight, microcephaly, upper limb abnormalities, and imperforate anus and for whom chromosome breakage analysis of patient cells revealed increased mitomycin C sensitivity. BRIP1 p.R848H alters a highly conserved residue in the catalytic DNA helicase domain. We show that BRIP1 p.R848H leads to a defect in helicase activity. Heterozygosity at this missense has been reported in multiple cancer patients but, in the absence of functional studies, classified as of unknown significance. Our results support that this mutation is pathogenic for Fanconi anemia in homozygotes and for increased cancer susceptibility in heterozygous carriers.

Original languageEnglish
Article numbera005652
JournalCold Spring Harbor molecular case studies
Issue number5
StatePublished - Oct 2020
Externally publishedYes


Dive into the research topics of 'Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities'. Together they form a unique fingerprint.

Cite this