Prenatal upper-limb mesomelia and 2q31.1 microdeletions affecting the regulatory genome (original) (raw)
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American Journal of Medical Genetics Part A, 2010
We present a newborn with multiple congenital abnormalities in whom array comparative genomic hybridization (aCGH) along with fluorescence in situ hybridization (FISH) revealed two distinct microdeletions on chromosomes 13q and 2q. Parental aCGH studies demonstrated that both deletions were inherited from the father who had, in addition, a third deletion on chromosome 6q. The proposita's paternal half-sister was also tested and found to have not only the 2q and 6q deletions, but also a duplication 17p that was subsequently discovered in the proposita's mother as well. aCGH studies in this family, notable for four discrete copy number variations (CNVs), underscore both the new complexities being revealed at a rapid pace as well as the increasing need for greater communication between clinicians and genetic laboratory professionals regarding genotype-phenotypic associations.
American Journal Medical Genetics
We describe three cases of a severe malformation syndrome in siblings of both sexes. The characteristic features observed were absent intrauterine ossification of an apparently normal cartilaginous spinal column; rib abnormalities, with unossified segments and posterior gaps; thoracic hypoplasia; and multiple intralobar nephrogenic rests in the kidneys. This syndrome can be identified in early pregnancy by ultrasound scans due to the lack of ossification of the thoraco-lumbar spine and its association with increased nuchal translucency thickness. We suggest that this is a newly recognized autosomal recessive syndrome. ß
The American Journal of Human Genetics, 2010
Segmental duplications, which comprise~5%-10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are~2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is~2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These characteristics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that microdeletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome.
Prenatal presentation of a rare genetic disorder: a clinical, autopsy and molecular correlation
Autopsy and Case Reports
Walker Warburg syndrome (WWS) lies at the severe end of the spectrum of the congenital muscular dystrophies. WWS is a congenital disorder of the O-glycosylation that disrupts in the post-translation modification of dystroglycan proteins. WWS is characterized by the involvement of the central nervous system and rarely by multisystem involvement. Next-generation sequencing discovered that multiple genes are associated with this disorder. FKTN is the rarest cause of WWS. We describe a clinical-autopsy report of a molecularly-confirmed WWS case presenting with ventriculomegaly, agenesis of the corpus callosum with a novel phenotype of Dandy-Walker malformation and unilateral multi-cystic kidney. The whole-exome sequencing confirmed a homozygous variant (c.411C>A) in the FKTN gene with a premature termination codon. This case emphasizes the importance of detailed postnatal phenotyping through an autopsy in any pregnancy with antenatally identified malformations. Obstetricians, pediatricians as well as fetal medicine experts need to counsel the parents and focus on preserving the appropriate sample for genetic testing. WWS, though rare deserves testing especially in the presence of positive family history. Dandy-Walker malformation is a novel feature and expands the phenotypic spectrum.
Need for Fetal Autopsy and Genetic Diagnosis in Fetal Limb Anomalies
Journal of Fetal Medicine, 2015
Improved antenatal imaging has led to increased detection rates of fetal limb anomalies. While they are nonlethal, they could be the first indication of an underlying genetic disorder. In the event of termination, postmortem and genetic evaluation are rarely performed, missing the opportunity to diagnose genetic disorders. The aim of the present study was to examine the utility of fetal autopsy in antenatally detected limb anomalies and to determine the incidence of genetic disorders in the same cohort. This was a retrospective evaluation of 59 cases. Only fetuses terminated for limb anomalies, either in isolation or in association with other features, were included. Cases terminated for lethal skeletal dysplasia and arthrogryposis multiplex congenita were excluded. Cases where limb defects were diagnosed after termination were also not included. The antenatal ultrasound records were compared to postmortem findings to determine the concordance rates. Chromosomal studies along with fetal autopsy were performed in all cases. Mutation analysis was also carried out where possible. Complete concordance between antenatal and postnatal findings was observed in 61 % of the cases. In 23.7 % of the cases, additional major anomalies were observed, the commonest being orofacial clefts. A genetic association was present in 62.7 % of the cases, of which, 25.4 % had an abnormal karyotype. Bilateral limb involvement and presence of associated features were strong predictors of genetic syndromes.
Prenatal Diagnosis, 2020
Objectives: To evaluate the correlation between aberrant right subclavian artery (ARSA), with or without other ultrasound abnormality, and risk factors for aneuploidies and chromosomal microarray analysis (CMA) results. Methods and materials: This was a multicentre study. Genetic analyses of foetuses diagnosed with ARSA were evaluated by CMA in the same laboratory. The clinical investigation included nuchal translucency, first and second trimester maternal serum screening, early and late second trimester foetal anatomic scans and foetal echocardiogram. Comparative Genomic Hybridization (CGH) Microarray analysis or Single Nucleotide Polymorphism (SNP) Array technology was used for CMA. Results: CMA results were available for 63 foetuses diagnosed with ARSA. No pathogenic variants were found among 36 foetuses with ARSA as an isolated finding. Additional ultrasound findings and/or risk factors for aneuploidies were present in 27 foetuses, of which 5 had pathogenic CMA results. Trisomy 21 (T21) was detected in a foetus with echogenic intracardiac focus (EIF), 22q11 deletion was detected in a foetus with EIF and 1:230 maternal serum screening increased risk for T21, 22q11 duplication was detected in a foetus with hypoplastic right kidney and choroid plexus cysts, and 22q11 deletion in a foetus with right aortic arch and clubfoot. In the fifth foetus, both 22q11 deletion and 1q21 duplication were detected by CMA. In addition to ARSA, abnormal nuchal translucency (4 mm) and ventricular septal defect were also present.