Marja Hietala

Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients’ lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm^-/- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.

Crying combined with miscellaneous gastrointestinal symptoms are typical symptoms of infant with food allergy, but are also common among children with abnormal neurological development. Mutations in KAT6A gene is known to cause a syndrome characterized by developmental delay, hypotonia, cardiac defects, microcephaly, specific facial features and early feeding problems. However, these feeding problems have not earlier been specified. We present the first reported case of a DBPCFC confirmed food allergy in a child with KAT6A mutation whose feeding problems resolved with elimination diet. The present case does not establish proof of cause, but highlights the importance of careful clinical diagnostics despite other possible causes for feeding problems. Recognizing that early feeding problems these patients regularly have might be caused by food allergy is important for outcome and quality of life for these patients.

Diagnostic analysis of patients with developmental disorders has improved over recent years largely due to the use of microarray technology. Array methods that facilitate copy number analysis have enabled the diagnosis of up to 20% more patients with previously normal karyotyping results. A substantial number of patients remain undiagnosed, however.