Prenatal diagnosis of trisomy 6q25.3-qter and monosomy 10q26.12-qter by array CGH in a fetus with an apparently normal karyotype.

We present the prenatal case of a 12.5-Mb duplication involving 6q25-qter and a 12.2-Mb deletion encompassing 10q26-qter diagnosed by aCGH, while conventional karyotype showed normal results. The genotype-phenotype correlation between individual microarray and clinical findings adds to the emerging atlas of chromosomal abnormalities associated with specific prenatal ultrasound abnormalities

Maternal cell-free DNA-based screening for fetal microdeletion and the importance of careful diagnostic follow-up.

BackgroundNoninvasive prenatal screening (NIPS) by next-generation sequencing of cell-free DNA (cfDNA) in maternal plasma is used to screen for common aneuploidies such as trisomy 21 in high risk pregnancies. NIPS can identify fetal genomic microdeletions; however, sensitivity and specificity have not been systematically evaluated. Commercial companies have begun to offer expanded panels including screening for common microdeletion syndromes such as 22q11.2 deletion (DiGeorge syndrome) without reporting the genomic coordinates or whether the deletion is maternal or fetal. Here we describe a phenotypically normal mother and fetus who tested positive for atypical 22q deletion via maternal plasma cfDNA testing.MethodsWe performed cfDNA sequencing on saved maternal plasma obtained at 11 weeks of gestation from a phenotypically normal woman with a singleton pregnancy whose earlier screening at a commercial laboratory was reported to be positive for a 22q11.2 microdeletion. Fluorescence in situ hybridization and chromosomal microarray diagnostic genetic tests were done postnatally.ConclusionNIPS detected a 22q microdeletion that, upon diagnostic workup, did not include the DiGeorge critical region. Diagnostic prenatal or postnatal testing with chromosomal microarray and appropriate parental studies to determine precise genomic coordinates and inheritance should follow a positive microdeletion NIPS result

Prenatal diagnosis of trisomy 6q25.3-qter and monosomy 10q26.12-qter by array CGH in a fetus with an apparently normal karyotype.

We present the prenatal case of a 12.5-Mb duplication involving 6q25-qter and a 12.2-Mb deletion encompassing 10q26-qter diagnosed by aCGH, while conventional karyotype showed normal results. The genotype-phenotype correlation between individual microarray and clinical findings adds to the emerging atlas of chromosomal abnormalities associated with specific prenatal ultrasound abnormalities

Prenatal diagnosis of trisomy 6q25.3‐qter and monosomy 10q26.12‐qter by array CGH

We present the prenatal case of a 12.5-Mb duplication involving 6q25-qter and a 12.2-Mb deletion encompassing 10q26-qter diagnosed by aCGH, while conventional karyotype showed normal results. The genotype–phenotype correlation between individual microarray and clinical findings adds to the emerging atlas of chromosomal abnormalities associated with specific prenatal ultrasound abnormalities

Maternal cell-free DNA-based screening for fetal microdeletion and the importance of careful diagnostic follow-up.

BackgroundNoninvasive prenatal screening (NIPS) by next-generation sequencing of cell-free DNA (cfDNA) in maternal plasma is used to screen for common aneuploidies such as trisomy 21 in high risk pregnancies. NIPS can identify fetal genomic microdeletions; however, sensitivity and specificity have not been systematically evaluated. Commercial companies have begun to offer expanded panels including screening for common microdeletion syndromes such as 22q11.2 deletion (DiGeorge syndrome) without reporting the genomic coordinates or whether the deletion is maternal or fetal. Here we describe a phenotypically normal mother and fetus who tested positive for atypical 22q deletion via maternal plasma cfDNA testing.MethodsWe performed cfDNA sequencing on saved maternal plasma obtained at 11 weeks of gestation from a phenotypically normal woman with a singleton pregnancy whose earlier screening at a commercial laboratory was reported to be positive for a 22q11.2 microdeletion. Fluorescence in situ hybridization and chromosomal microarray diagnostic genetic tests were done postnatally.ConclusionNIPS detected a 22q microdeletion that, upon diagnostic workup, did not include the DiGeorge critical region. Diagnostic prenatal or postnatal testing with chromosomal microarray and appropriate parental studies to determine precise genomic coordinates and inheritance should follow a positive microdeletion NIPS result

Maternal cell-free DNA–based screening for fetal microdeletion and the importance of careful diagnostic follow-up

BACKGROUND: Noninvasive prenatal screening (NIPS) by next-generation sequencing of cell free DNA (cfDNA) in maternal plasma is used to screen for common aneuploidies such as trisomy 21, in high risk pregnancies. NIPS can identify fetal genomic microdeletions, however sensitivity and specificity have not been systematically evaluated. Commercial companies have begun to offer expanded panels including screening for common microdeletion syndromes such as 22q11.2 deletion (DiGeorge syndrome) without reporting the genomic coordinates or whether the deletion is maternal or fetal. Here we describe a phenotypically normal mother and fetus that tested positive for atypical 22q deletion via maternal plasma cell free DNA testing. METHODS: We performed cfDNA sequencing on saved maternal plasma obtained at 11 weeks of gestation from a phenotypically normal woman with a singleton pregnancy whose earlier screening at a commercial laboratory was reported to be positive for a 22q11.2 microdeletion. FISH and chromosomal microarray diagnostic genetic tests were done postnatally. CONCLUSION: NIPS detected a 22q microdeletion that upon diagnostic work up, did not include the DiGeorge critical region. Diagnostic prenatal or postnatal testing with chromosomal microarray and appropriate parental studies to determine precise genomic coordinates and inheritance should follow a positive microdeletion NIPS result

Expansion of phenotype and genotypic data in CRB2-related syndrome

Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype