Nager syndrome is a rare, complex malformation syndrome, for which there is limited information on prenatal genetic testing. Clinical diagnosis of Nager syndrome, which can be caused by deletions encompassing SF3B4 gene, is possible prenatally. Prenatal chromosomal microarray can aid genotype‐phenotype correlation in pregnancies with structural abnormalities seen on ultrasound.
Background
Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. However, establishing its molecular diagnosis remains challenging. Chromosomal breakage analysis is the gold standard diagnostic test for this disease. Nevertheless, molecular analysis is always required for the identification of pathogenic alterations in the FA genes.
Results
We report here on a family with FA diagnosis in two siblings. Mitomycin C (MMC) test revealed high level of chromosome breaks and radial figures. In both children, array—Comparative Genomic Hybridization (aCGH) showed maternally inherited 16q24.3 deletion, including FANCA gene, and next generation sequencing (NGS) disclosed paternally inherited novel variants in the FANCA gene—Asn1113Tyr and Ser890Asn. A third sibling was shown to be a carrier of FANCA deletion only.
Conclusions
Although genetic testing in FA patients often requires a multi-method approach including chromosome breakage test, aCGH, and NGS, every effort should be made to make it available for whole FA families. This is not only to confirm the clinical diagnosis of FA in affected individuals, but also to enable identification of carriers of FA gene(s) alterations, as it has implications for diagnostic and genetic counselling process.
BackgroundBalanced complex translocations (BCTs) are rare events, they may result in reproductive failures: spontaneous abortions, missed abortions, stillbirths, congenital malformations in children, and male infertility. BCTs belong to the group of complex chromosome rearrangements (CCRs) – up to date about 260 cases were described.ResultsThe described patient and her husband were referred to genetic counseling clinic because of four reproductive failures. GTG-banded chromosome analysis revealed presence of apparently balanced complex translocation t(2;5;13), which was verified and confirmed by molecular cytogenetics with single copy probes. This complex aberration was most likely responsible for reproductive failures in our patient. Since no high resolution molecular karyotyping (microarrays) was used, this rearrangement can only be considered to be balanced at cytogenetic level.DiscussionDue to small number of reported cases of CCRs/BCTs and individual as well as unique character of such rearrangements, genetic counseling for CCRs carriers is complex and requires detailed pedigree analysis, as well as extended clinical and genetic testing.
Deletions of the PAX3 gene have been rarely reported in the literature. Mutations of this gene are a common cause of Waardenburg syndrome type 1 and 3. We report a 16 year old female presenting hearing loss and normal intellectual development, without major features of Waardenburg syndrome type 1, and without family history of the syndrome. Her phenotype, however, overlaps with features of craniofacial-deafness-hand syndrome. Microarray analysis showed ~862 kb de novo deletion at 2q36.1 including PAX3. The above findings suggest that the rearrangement found in our patient appeared de novo and with high probability is a cause of her phenotype.
Background: Fanconi anemia is a rare genetic disorder caused by mutations in genes which protein products are involved in replication, cell cycle control and DNA repair. It is characterized by congenital malformations, bone marrow failure, and high risk of cancer. The diagnosis is based on morphological and hematological abnormalities such as pancytopenia, macrocytic anaemia and progressive bone marrow failure. Genetic examination, often very complex, includes chromosomal breakage testing and mutational analysis. Case presentation: We present a child with clinical diagnosis of Fanconi anemia. Although morphological abnormalities of skin and bones were present from birth, diagnosis was only suspected at the age of 8. Chromosome breakage test in patient's lymphocytes showed increased level of aberrations (gaps, chromatid breaks, chromosome breaks, radial figures and rearrangements) compared to control. Next generation sequencing revealed presence of two pathogenic variants in FANCA gene, one of which was not previously reported. Conclusions: The article provides additional supportive evidence that compound biallelic mutations of FANCA are associated with Fanconi anemia. It also illustrates the utility of combination of cytogenetic and molecular tests, together with detailed clinical evaluation in providing accurate diagnosis of Fanconi anemia. This report, to the best of our knowledge, describes the first fully diagnosed FA patient in Polish population.
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