RESUMO
Distal trisomy or duplication of 15q is a very rare chromosomal disorder; most of the previously reported cases were derived from unbalanced translocations involving chromosome 15 and another chromosome, whereas other mechanisms (e.g. duplication) have rarely been reported. We herein report a very rare prenatal case of a partial 15q trisomy, a 42.64-Mb duplication of 15q22.2-q26.3, arising from a maternal pericentric inversion of chromosome 15 (p11q22) that was not the result of an unbalanced translocation or duplication, and was not associated with concomitant partial monosomy. Fetal ultrasound revealed isolated thickened nuchal translucency at 12 weeks and multiple abnormalities in the second trimester, including early growth restriction, unilateral ventriculomegaly, narrow cavum septi pellucidi with hypoplasia of the corpus callosum, unilateral postaxial polydactyly, clenched hands and clubfoot with clawing of the toes, and a particular general dysplastic and hypotrophic aspect of the heart. The distinctive aspects of the present case may help to refine the phenotype associated with distal duplication 15q. To the best of our knowledge, this is the first report of a prenatal diagnosis with a 15q22.2-q26.3 duplication that did not result from an unbalanced translocation and did not have a concomitant monosomic component.
RESUMO
BACKGROUND: Non-invasive prenatal testing (NIPT) has been widely adopted for the detection of fetal aneuploidies and microdeletion syndromes, nevertheless, limited clinical utilization has been reported for the non-invasive prenatal screening of monogenic diseases. In this study, we present the development and validation of a single comprehensive NIPT for prenatal screening of chromosomal aneuploidies, microdeletions and 50 autosomal recessive disorders associated with severe or moderate clinical phenotype. RESULTS: We employed a targeted capture enrichment technology powered by custom TArget Capture Sequences (TACS) and multi-engine bioinformatics analysis pipeline to develop and validate a novel NIPT test. This test was validated using 2033 cell-fee DNA (cfDNA) samples from maternal plasma of pregnant women referred for NIPT and paternal genomic DNA. Additionally, 200 amniotic fluid and CVS samples were used for validation purposes. All NIPT samples were correctly classified exhibiting 100% sensitivity (CI 89.7-100%) and 100% specificity (CI 99.8-100%) for chromosomal aneuploidies and microdeletions. Furthermore, 613 targeted causative mutations, of which 87 were unique, corresponding to 21 monogenic diseases, were identified. For the validation of the assay for prenatal diagnosis purposes, all aneuploidies, microdeletions and point mutations were correctly detected in all 200 amniotic fluid and CVS samples. CONCLUSIONS: We present a NIPT for aneuploidies, microdeletions, and monogenic disorders. To our knowledge this is the first time that such a comprehensive NIPT is available for clinical implementation.
RESUMO
Prenatal diagnosis was requested for an undiagnosed eye disease showing X-linked inheritance in a family. No medical records existed for the affected family members. Mapping of the X chromosome and candidate gene mutation screening identified a c.C267A[p.F89L] mutation in NPD previously described as possibly causing Norrie disease. The detection of the c.C267A[p.F89L] variant in another unrelated family confirms the pathogenic nature of the mutation for the Norrie disease phenotype. Gene mapping, haplotype analysis, and candidate gene screening have been previously utilized in research applications but were applied here in a diagnostic setting due to the scarcity of available clinical information. The clinical diagnosis and mutation identification were critical for providing proper genetic counseling and prenatal diagnosis for this family.