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A Dutch Fanconi Anemia FANCC Founder Mutation in Canadian Manitoba Mennonites.

ABSTRACT: Fanconi anemia (FA) is a recessive DNA instability disorder associated with developmental abnormalities, bone marrow failure, and a predisposition to cancer. Based on their sensitivity to DNA cross-linking agents, FA cells have been assigned to 15 complementation groups, and the associated genes have been identified. Founder mutations have been found in different FA genes in several populations. The majority of Dutch FA patients belongs to complementation group FA-C. Here, we report 15 patients of Dutch ancestry and a large Canadian Manitoba Mennonite kindred carrying the FANCC c.67delG mutation. Genealogical investigation into the ancestors of the Dutch patients shows that these ancestors lived in four distinct areas in The Netherlands. We also show that the Dutch and Manitoba Mennonite FANCC c.67delG patients share the same haplotype surrounding this mutation, indicating a common founder.

SUBMITTER: de Vries Y

PROVIDER: S-EPMC3372307 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A Dutch Fanconi Anemia FANCC Founder Mutation in Canadian Manitoba Mennonites.

de Vries Yne Y Lwiwski Nikki N Levitus Marieke M Kuyt Bertus B Israels Sara J SJ Arwert Fré F Zwaan Michel M Greenberg Cheryl R CR Alter Blanche P BP Joenje Hans H Meijers-Heijboer Hanne H

Anemia 20120604

Fanconi anemia (FA) is a recessive DNA instability disorder associated with developmental abnormalities, bone marrow failure, and a predisposition to cancer. Based on their sensitivity to DNA cross-linking agents, FA cells have been assigned to 15 complementation groups, and the associated genes have been identified. Founder mutations have been found in different FA genes in several populations. The majority of Dutch FA patients belongs to complementation group FA-C. Here, we report 15 patients ...[more]

PMID: 22701786

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Project description:BackgroundFanconi anemia (FA) is phenotypically diverse, hereditary condition associated with bone marrow failure, multiple physical abnormalities, and an increased susceptibility to the development of malignancies. Less recognized manifestations of FA include endocrine abnormalities. International discourse has highlighted that these abnormalities are widespread among children and adults with FA. To date there has been no systematic study that has evaluated the endocrine abnormalities in a cohort of patients with FA, homozygous for a founder mutation (c.637_643del (p.Tyr213Lysfs*6)) in FANCG. The objectives of the study were to evaluate endocrine gland function in patients with FA of a single FA genotype, and to determine the frequency and nature of endocrine abnormalities in this group.MethodsCross-sectional, descriptive study of 24 South African patients of African ancestry with FA (homozygous for a FANCG founder mutation). Outcomes measured included growth, pubertal status, growth hormone axis screening, thyroid gland function, glucose and insulin metabolism and bone age (BA).ResultsEndocrine dysfunction was present in 70.8% (17 of 24), including abnormal insulin-like growth factor 1 (IGF-1)/insulin-like growth factor-binding protein 3 (IGFBP-3) in 25.0% (6 of 24), insulin resistance in 41.7% (10 of 24), abnormal thyroid function in 16.7% (4 of 24) and short stature in 45.8% (11 of 24). No abnormalities of glucose metabolism were identified. Abnormal pubertal status was seen in three males (12.5%). Abnormal BAs were present in 34.8% (8 of 23).ConclusionEndocrine abnormalities occur at a high frequency in patients with FA, homozygous for a FANCG founder mutation, similar to other FA cohorts. Our data are specific to FA patients with a single genotype, and therefore provide the first genotype-phenotype information on endocrine abnormalities in South African patients, homozygous for a FANCG founder mutation. Recommendations regarding endocrine screening in this patient subgroup are made, including, but not limited to, baseline testing of thyroid function, fasted insulin and glucose, and IGF-1 and IGFBP-3.

Dataset Information

A Dutch Fanconi Anemia FANCC Founder Mutation in Canadian Manitoba Mennonites.

Publications

A Dutch Fanconi Anemia FANCC Founder Mutation in Canadian Manitoba Mennonites.

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