Chromosome 22q11.2 deletion syndrome: prenatal diagnosis,array comparative genomic hybridization characterization using uncultured amniocytes and literature review

We present prenatal diagnosis of de novo 22q11.2 microdeletion syndrome using uncultured amniocytes in a pregnancy with conotruncal heart malformations in the fetus. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of TBX1, COMT, UFD1L, GNB1L and MED15 in the deleted region. We review the literature of chromosomal loci and genes responsible for conotruncal heart malformations and tetralogy of Fallot.     

Chromosome 18p deletion syndrome presenting holoprosencephaly and premaxillary agenesis: Prenatal diagnosis and aCGH characterization using uncultured amniocytes

We present prenatal diagnosis of a de novo distal 18p deletion involving 14.06 Mb at 18p11.32–p11.21 by aCGH using uncultured amniocytes in a pregnancy with fetal holoprosencephaly and premaxillary agenesis. QF-PCR analysis showed that distal 18p deletion was from maternal origin. Metaphase FISH analysis confirmed haploinsufficiency of TGIF. We discuss the functions of the genes that are deleted within this region. The present case shows the usefulness of applying aCGH on uncultured amniocytes for rapid aneuploidy diagnosis in cases with prenatally detected fetal structural abnormalities.     

Prenatal diagnosis and molecular cytogenetic characterization of a de novo proximal interstitial deletion of chromosome 4p (4p15.2→p14)

We present prenatal diagnosis of de novo proximal interstitial deletion of chromosome 4p (4p15.2→p14) and molecular cytogenetic characterization of the deletion using uncultured amniocytes. We review the phenotypic abnormalities of previously reported patients with similar proximal interstitial 4p deletions, and we discuss the functions of the genes of RBPJ, CCKAR, STIM2, PCDH7 and ARAP2 that are deleted within this region.     

Cri-du-chat (5p-) syndrome presenting with cerebellar hypoplasia and hypospadias: Prenatal diagnosis and aCGH characterization using uncultured amniocytes

We present prenatal diagnosis of a de novo distal deletion involving 5p(5p15.1 → pter) using uncultured amniocytes in a pregnancy with cerebellar hypoplasia, hypospadias and facial dysmorphisms in the fetus. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of CTNND2, SEMA5A, TERT, SRD5A1 and TPPP. We speculate that haploinsufficiency of SRD5A1 and TPPP may be responsible for hypospadias and cerebellar hypoplasia, respectively, in this case.     

Prenatal diagnosis and molecular cytogenetic characterization of a de novo interstitial deletion of 7q (7q22.1 → q31.1)

We present prenatal diagnosis and molecular cytogenetic characterization of de novo interstitial deletion of 7q (7q22.1 → q31.1) by aCGH, FISH and QF-PCR in a fetus with an abnormal maternal serum screening result and ultrasound findings of facial cleft and hypogenitalism. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of ZKSCAN5, ARPC1A, CYP3A43, RELN, LAMB1, IMMP2L and DOCK4 in this case.     

Phenotypic expansion of the interstitial 16p13.3 duplication: A case report and review of the literature

Genotype–phenotype analysis of at least 25 individuals with interstitial 16p13.3 duplications defines a recognizable syndrome associated with duplication of a critical Rubinstein–Taybi region encompassing only the CREBBP gene. Nevertheless, variable or incompletely penetrant phenotype has been reported previously. We here report a case of a 5-year old boy with a recognizable phenotype of this syndrome, including intellectual disability, mild arthrogryposis, small and proximally implanted thumbs and characteristic facial features. In addition, growth delay, microcephaly and distinguishable structural brain MRI abnormalities were observed. A de novo 1.5 Mb interstitial duplication of 16p13.3 was detected by SNP-array and fluorescence in situ hybridization (FISH). Short tandem repeat polymorphism (STRP) analysis with marker D16S475 indicated that the duplication was formed before maternal meiosis II. Our findings highlight the variable clinical features and further expand the phenotypic spectrum correlated with this lately proposed syndrome.     

Mosaic small supernumerary marker chromosome 1 at amniocentesis: Prenatal diagnosis,molecular genetic analysis and literature review

We present prenatal diagnosis and molecular cytogenetic analysis of mosaic small supernumerary marker chromosome 1 [sSMC(1)]. We review the literature of sSMC(1) at amniocentesis and chromosome 1p21.1-p12 duplication syndrome. We discuss the genotype–phenotype correlation of the involved genes of ALX3, RBM15, NTNG1, SLC25A24, GPSM2, TBX15 and NOTCH2 in this case.     

Chromosome 19p13.3 deletion in a child with Peutz-Jeghers syndrome, congenital heart defect, high myopia, learning difficulties and dysmorphic features: Clinical and molecular characterization of a new contiguous gene syndrome

The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girl with PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome.     

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 22 associated with cat eye syndrome

We present prenatal diagnosis of mosaicism for a small supernumerary marker chromosome (sSMC) derived from chromosome 22 associated with cat eye syndrome (CES) using cultured amniocytes in a pregnancy with fetal microcephaly, intrauterine growth restriction, left renal hypoplasia, total anomalous pulmonary venous return with dominant right heart and right ear deformity. The sSMC was bisatellited and dicentric, and was characterized by multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). The SALSA MLPA P250-B1 DiGeorge Probemix showed duplication of gene dosage in the CES region. aCGH showed a 1.26-Mb duplication at 22q11.1–q11.21 encompassing CECR1–CECR7. The sSMC was likely inv dup(22) (q11.21). Prenatal diagnosis of an sSMC(22) at amniocentesis should alert CES. MLPA, aCGH and fetal ultrasound are useful for rapid diagnosis of CES in case of prenatally detected sSMC(22).     

Ring chromosome 21 presenting with sacrococcygeal teratoma: Prenatal diagnosis,molecular cytogenetic characterization and literature review

We present perinatal findings and molecular cytogenetic characterization of a prenatally detected sacrococcygeal teratoma associated with mosaic r(21). This is the first report of mosaic r(21) presenting with a fetal sacrococcygeal teratoma. We discuss cytogenetic abnormalities associated with fetal sacrococcygeal teratomas.     

Prenatal diagnosis and molecular cytogenetic characterization of de novo pure partial trisomy 6p associated with microcephaly,craniosynostosis and abnormal maternal serum biochemistry

We present prenatal diagnosis and molecular cytogenetic characterization of de novo pure trisomy 6p22.3 → p25.3 encompassing BMP6 in a fetus associated with microcephaly and craniosynostosis on prenatal ultrasound, abnormal maternal serum biochemistry of a low PAPP-A level in the first-trimester combined test, and a karyotype of 46,XX,der(22)t(6;22)(p22.3;p13)dn. The present case demonstrates the usefulness of rapid prenatal identification of the origin of the extra chromosome material on the short arm of an acrocentric chromosome by spectral karyotyping, fluorescence in situ hybridization and array comparative genomic hybridization. We review the phenotypic abnormality of craniosynostosis in previously reported patients with partial trisomy 6p. We discuss the genotype–phenotype correlation of the involved gene of BMP6 in this case.     

Prenatal diagnosis and molecular cytogenetic characterization of mosaic ring chromosome 13

We present prenatal diagnosis and molecular cytogenetic characterization of de novo mosaic r(13). A 32-year-old woman underwent amniocentesis at 18 weeks of gestation because of maternal anxiety. Amniocentesis revealed a karyotype of 46,XY,r(13)[33]/45,XY,-13[19]. aCGH on uncultured amniocytes at repeated amniocentesis detected a 4.22-Mb deletion at 13q34. Interphase FISH on 100 uncultured amniocytes showed the ratio of r(13):-13:idic r(13) as 85%:13%:2%. The cord blood had a karyotype of 46,XY,r(13)[91]/46,XY,idic r(13)[6]/45,XY,-13[3]. The placenta had a karyotype of 46,XY,mar(13)[31]/45,XY,-13[3]. Metaphase FISH confirmed that the marker chromosomes in placenta were derived from chromosome 13. aCGH on cultured placental cells detected a 77.81-Mb deletion at 13q13.3–q34. The fetus postnatally manifested facial dysmorphism. Prenatal diagnosis of r(13) should alert mosaicism for deletion/duplication of r(13) and distal 13q deletion. Fetoplacental chromosomal discrepancy of r(13) may exist in case of mosaic r(13) detected by amniocentesis.     

3q26.31–q29 duplication and 9q34.3 microdeletion associated with omphalocele,ventricular septal defect,abnormal first-trimester maternal serum screening and increased nuchal translucency: Prenatal diagnosis and aCGH characterization

We present prenatal diagnosis and array comparative genomic hybridization characterization of 3q26.31–q29 duplication and 9q34.3 microdeletion in a fetus with omphalocele, ventricular septal defect, increased nuchal translucency, abnormal first-trimester maternal screening and facial dysmorphism with distinct features of the 3q duplication syndrome and Kleefstra syndrome. The 26.61-Mb duplication of 3q26.31–q29 encompasses EPHB3, CLDN1 and CLDN16, and the 972-kb deletion of 9q34.3 encompasses EHMT1. We review the literature of partial trisomy 3q associated with omphalocele and discuss the genotype–phenotype correlation in this case.     

De novo trisomy 20p characterized by array comparative genomic hybridization: Report of a novel case and review of the literature

We report on a boy with speech delay, mental retardation, motor clumsiness, hyperactivity, dysmorphic facial features, brachytelephalangy and short stature. Electrocardiogram, echocardiography, renal ultrasound, electroencephalogram, fundoscopic exam and auditory brainstem responses were all normal. Brain magnetic resonance imaging showed a left temporal arachnoid cyst and a small pineal gland cyst.     

Phenotype and Micro-array characterization of duplication 11q22.1-q25 and review of the literature

Partial duplication of 11q is related to several malformations like growth retardation, intellectual disability, hypoplasia of corpus callosum, short nose, palate defects, cardiac, urinary tract abnormalities and neural tube defects. We have studied the clinical and molecular characteristics of a patient with severe intellectual disabilities, dysmorphic features, congenital inguinal hernia and congenital cerebral malformation which is referred to as cytogenetic exploration. We have used FISH and array CGH analysis for a better understanding of the double chromosomic aberration involving a 7p microdeletion along with a partial duplication of 11q due to adjacent segregation of a paternal reciprocal translocation t(7;11)(p22;q21) revealed after banding analysis. The patient's karyotype formula was: 46,XY,der(7)t(7;11)(p22;q21)pat. FISH study confirmed these rearrangement and array CGH technique showed precisely the loss of at least 140 Kb on chromosome7p22.3pter and 33.4 Mb on chromosome11q22.1q25. Dysmorphic features, severe intellectual disability and brain malformations could result from the 11q22.1q25 trisomy. Our study provides an additional case for better understanding and delineating the partial duplication 11q.     

De novo 3q22.1 q24 deletion associated with multiple congenital anomalies,growth retardation and intellectual disability

We describe a boy with a de novo deletion of 15.67 Mb spanning 3q22.1q24. He has bilateral micropthalmia, ptosis, cleft palate, global developmental delay and brain, skeletal and cardiac abnormalities. In addition, he has bilateral inguinal hernia and his right kidney is absent. We compare his phenotype with seven other patients with overlapping and molecularly defined interstitial 3q deletions. This patient has some phenotypic features that are not shared by the other patients. More cases with smaller deletions defined by high resolution aCGH will enable better genotype–phenotype correlations and prioritizing of candidate genes for the identification of pathways and disease mechanisms.