Semilobar holoprosencephaly prenatal diagnosis: an unexpected complex rearrangement in a de novo apparently balanced reciprocal translocation on karyotype

We report a semilobar holoprosencephaly (HPE) in a post-intracytoplasmic-sperm-injection pregnancy. It was suggested by ultrasonography (US), documented on karyotype, identified with magnetic resonance imaging (MRI), established after birth and confirmed on post-mortem autopsy. An amniocentesis revealed a de novo apparently balanced reciprocal translocation 46,XY, t(7;8) (q31.3;q12). Fluorescence in situ hybridization (FISH) identified a deletion in the region of the Sonic Hedgehog gene (SHH) on der(8); nevertheless, the subtelomeric regions for chromosomes 7 and 8 were present. The parents decided to continue the pregnancy; a boy was born and survived for 3 days. The brain autopsy confirmed the semilobar HPE previously noted on US and MRI. Further, band-specific FISH revealed, in addition to SHH deletion, the presence of an inversion in the 7q translocated material on der(8). The parents' karyotypes were normal. An unexpected complex rearrangement was present in a de novo apparently balanced reciprocal translocation in a semilobar HPE.     

Maternal complex chromosome rearrangements involving five chromosomes 1, 4, 10, 12 and 20 ascertained through a del(4)(p14p15) detected in a mother's first affected daughter

Complex chromosomal rearrangements, defined as exchanges between three or more chromosomes, are very rare aberrations in human chromosomal pathology. We present a case of a complex, apparently balanced maternal chromosome rearrangement involving five different chromosomes (1, 4, 10, 12 and 20) and six breakpoints ascertained through a deletion of the short arm of chromosome 4 [del(4)(p14p15)] detected in a mother's affected 2-year old daughter.     

Prenatal diagnosis of de novo t(2;18;14)(q33.1;q12.2;q31.2), dup(5)(q34q34), del(7)(p21.1p21.1), and del(10)(q25.3q25.3) and a review of the prenatally ascertained de novo apparently balanced complex and multiple chromosomal rearrangements

OBJECTIVES: To present the prenatal diagnosis of a de novo complex chromosomal rearrangement (CCR) associated with de novo interstitial deletions and duplication and to review the literature. CASE AND METHODS: Amniocentesis was performed at 18 weeks' gestation because of an increased risk for Down syndrome based on maternal serum alpha-fetoprotein and human chorionic gonadotrophin screening. Amniocentesis revealed a karyotype of 46,XY,t(2;18;14)(q33.1;q12.2;q31.2),dup(5)(q34q34),del(7)(p21.1p21.1), del(10)(q25.3q25.3). The parental karyotypes were normal. The pregnancy was terminated. The fetus manifested facial dysmorphism, clinodactyly of both hands, and hypoplasia of the left great toe. Spectral karyotyping (SKY), cytogenetic polymorphism, and polymorphic DNA markers were used to investigate the imbalances and the origin of the de novo aberrant chromosomes. RESULTS: SKY showed a three-way CCR. Cytogenetic polymorphism investigation of the derivative chromosome 14 of the fetus and the parental chromosomes 14 determined the maternal origin of the translocation. Polymorphic DNA marker analysis confirmed the maternal origin of the de novo interstitial deletions and duplication. No cryptic imbalance at or near the breakpoints of the CCR was detected by the molecular analysis. CONCLUSIONS: De novo apparently balanced CCRs may be associated with imbalances in other chromosomes. We suggest further investigation and re-evaluation of cryptic or subtle imbalances in all cases classified as de novo apparently balanced CCRs.     

Prenatal diagnosis of a 9q34.3 microdeletion by array-CGH in a fetus with an apparently balanced translocation

OBJECTIVES: Use high-resolution genome analysis to clarify the genomic integrity in a fetus with a cytogenetically balanced translocation t(2;9)(q11.2;q34.3). METHODS: High resolution molecular cytogenetic analyses including G-banded chromosome analysis, fluorescence in situ hybridization (FISH), and array-comparative genomic hybridization (CGH) were performed on cultured cells, and DNA extracted from chorionic villus sample (CVS), amniotic fluid cells and fetal tissue. In addition, a custom fosmid-based tiling path 9q34.3 microarray with a resolution of 35-40 kb was used for array-CGH. RESULTS: GTG-banding analysis showed an apparently balanced de novo translocation between the long arms of chromosomes 2 and 9; t(2;9)(q11.2;q34.3). Array-CGH using a targeted chromosomal microarray analysis (CMA) uncovered a submicroscopic deletion of the subtelomeric region of 9q34.3 revealing the unbalanced nature of the rearrangement. These results were confirmed independently by FISH. The deletion was delimited to 2.7 Mb in size using the 9q34.3 fosmid-based tiling path array-CGH. CONCLUSION: Array-CGH is a powerful tool for rapid detection of genomic imbalances associated with microdeletion/duplication syndromes and for the evaluation of de novo apparently balanced translocation to enable high-resolution genomic analysis at the breakpoints. Prenatal diagnosis of chromosomal rearrangements involving dosage-sensitive genomic regions is an important adjuvant to prenatal care and provides more accurate information for counseling and informed decision making.     

Association of autosomal dominant cleft lip and palate and translocation 6p23;9q22.3.

Orofacial clefting (OFC) is genetically complex in that no single gene defect is responsible for all forms. We have identified a family who exhibit autosomal dominant orofacial clefting together with some features of ectodermal dysplasia. In this family there is concordance between these features and an apparently balanced translocation t(6;9)(p23;q22.3) which raises the possibility that a locus for one form of orofacial clefting may be located at one of the translocation breakpoints. Fluorescent in situ hybridization has shown that a candidate gene for OFC, which maps to distal 6p, is located on the derived chromosome 9 in affected individuals from this family. Further characterization of the translocation breakpoints and of their relationship with the candidate gene will determine whether a gene important for normal facial and/or ectodermal development is disrupted in this family.     

Analysis of a de novo complex chromosome rearrangement involving chromosomes 4, 11, 12 and 13 and eight breakpoints by conventional cytogenetic, fluorescence in situ hybridization and spectral karyotyping

A complex chromosome rearrangement (CCR) with eight breakpoints resulting in four derivative chromosomes (4, 11, 12 and 13) was detected prenatally in a male fetus of a twin pregnancy. The karyotype of the female second fetus was normal. The apparently balanced de novo CCR was identified by classical cytogenetic methods and fluorescence in situ hybridization (FISH). We compared these findings with results from spectral karyotyping (SKY).     

Midline defects in deletion 18p syndrome: clinical and molecular characterization of three patients

The phenotype of monosomy 18p varies widely, the main clinical manifestations being mental and growth retardation, and craniofacial dysmorphism. Clinical features also include growth hormone (GH) deficiency, or holoprosencephaly (HPE). Haploinsufficiency for TGIF, mapped to 18p11.3, is not generally sufficient to cause HPE. To perform a genotype-phenotype correlation, and delineate the region involved in GH deficiency, we carried out a molecular characterization of the 18p deletions, in three patients with midline defects. Two unrelated children, a 7-month-old girl and a 2-month-old boy had del(18p) syndrome and GH deficiency. In addition, the boy had HPE. HPE genes, SHH, ZIC2, SIX3, and TGIF, were tested by denaturing high-performance liquid chromatography and quantitative multiplex of PCR short fluorescent fragments analyses. A deletion of TGIF was confirmed, without any associated mutation for the tested HPE genes, suggesting the role of other genetic or environmental factors. The third patient was his moderately retarded mother. A set of chromosome 18p-specific BACs clones was used as fluorescence in-situ hybridization probes to define the breakpoints. Recently, it was found that there seem to be a breakpoint cluster in the centromeric region at 18p11.1, which was not observed in our patients. The girl was found to have a deletion of 10.3 Mb, with a breakpoint in 18p11.22. The boy and his mother had a smaller deletion (8 Mb), with a breakpoint in 18p11.23. These findings suggest that the distal region on 18p is involved in the main clinical features, and GH deficiency, in 18p deletions.     

De-novo balanced translocation between 7q31 and 10p14 in a girl with central precocious puberty, moderate mental retardation, and severe speech impairment

No causative gene has been found for idiopathic central precocious puberty; and FOXP2, located in 7q31, is the only known gene for speech and language disturbances. We report a girl with central precocious puberty, moderate mental retardation, and severe speech impairment; accompanied by a de-novo balanced translocation between 7q31 and 10p14. Physical mapping through molecular cytogenetic investigations demonstrated the breakpoints of 7q31 and 10p14 within a bacterial artificial chromosome (BAC) clone RP11-124G5 and a cosmid clone derived from a BAC clone RP11-1122C18, respectively. FOXP2 was found to be localized approximately 500 kb distant from the centromeric end of the disrupted BAC RP11-124G5 at the 7q31 breakpoint. Speech impairment in the girl might be derived from dysfunction of FOXP2 by a position effect of the 7q31 translocation breakpoint.     

Inv dup del(10q): identification by fluorescence in situ hybridization and array comparative genomic hybridization in a fetus with two concurrent chromosomal rearrangements

ObjectiveTo present molecular cytogenetic characterization of an inverted duplication with terminal deletion of 10q, or inv dup del(10q) in a fetus with two concurrent chromosomal rearrangements.Materials, Methods and ResultsA 39-year-old woman underwent amniocentesis at 20 weeks of gestation because of advanced maternal age. Amniocentesis revealed a der(10) with additional material at the end of the long arm of chromosome 10, a der(9) and a der(22). Parental karyotypes were normal. A de novo unbalanced complex chromosomal rearrangement (CCR) was diagnosed by conventional cytogenetics, but the breakpoints could not be defined. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. Postnatal analysis of fetal tissues using spectral karyotyping, fluorescence in situ hybridization, multicolor banding, and array-comparative genomic hybridization identified an inv dup del(10q) with an inverted duplication of 10q25.1→q26.2 and a terminal deletion of 10q26.2→qter, and a balanced reciprocal translocation between chromosomes 9 and 22. Microsatellite analysis determined a paternal origin of the inv dup del(10q). The karyotype of the fetus was 46,XX,t(9;22)(p23;q13),der(10)del(10)(q26.2) dup(10)(q26.2q25.1)dn.ConclusionA de novo inv dup del(10q) can be associated with a concurrent de novo balanced reciprocal translocation and should be differentiated from an unbalanced CCR by molecular cytogenetic techniques.     

Prenatal diagnosis of partial monosomy 18p(18p11.2-->pter) and trisomy 21q(21q22.3-->qter) with alobar holoprosencephaly and premaxillary agenesis

A prenatal diagnosis of partial monosomy 18p(18p11.2-->pter) and trisomy 21q(21q22.3-->qter) in a fetus with alobar holoprosencephaly (HPE) and premaxillary agenesis (PMA) but without the classical Down syndrome phenotype is reported. A 27-year-old primigravida woman was referred for genetic counselling at 21 weeks' gestation due to sonographic findings of craniofacial abnormalities. Level II ultrasonograms manifested alobar HPE and median orofacial cleft. Cytogenetic analysis and fluorescence in situ hybridization (FISH) on cells obtained from amniocentesis revealed partial monosomy 18p and a cryptic duplication of 21q,46,XY,der(18)t(18;21)(p11.2;q22.3), resulting from a maternal t(18;21) reciprocal translocation. The breakpoints were ascertained by molecular genetic analysis. The pregnancy was terminated. Autopsy showed alobar HPE with PMA, pituitary dysplasia, clinodactyly and classical 18p deletion phenotype but without the presence of major typical phenotypic features of Down syndrome. The phenotype of this antenatally diagnosed case is compared with those observed in six previously reported cases with monosomy 18p due to 18;21 translocation. The present study is the first report of concomitant deletion of HPE critical region of chromosome 18p11.3 and cryptic duplication of a small segment of distal chromosome 21q22.3 outside Down syndrome critical region. The present study shows that cytogenetic analyses are important in detecting chromosomal aberrations in pregnancies with prenatally detected craniofacial abnormalities, and adjunctive molecular investigations are useful in elucidating the genetic pathogenesis of dysmorphism.     

Wolf-Hirschhorn (4p-) syndrome: prenatal diagnosis, molecular cytogenetic characterization and association with a 1.2-Mb microduplication at 8p22-p21.3 and a 1.1-Mb microduplication at 10p15.3 in a fetus with an apparently pure 4p deletion

ObjectiveTo present prenatal diagnosis and molecular cytogenetic characterization of Wolf-Hirschhorn syndrome (WHS) associated with microduplications at 8p and 10p in a fetus with an apparently pure 4p deletion.Case ReportA 35-year-old gravida 2, para 1 woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Her husband was 38 years of age. There was no family history of congenital malformations. Amniocentesis revealed a karyotype of 46,XY,del(4p16.1). The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) analysis revealed a 6.5-Mb deletion at 4p16.3-p16.1, a 1.2-Mb microduplication at 8p22-p21.3, and a 1.1-Mb microduplication at 10p15.3, or arr cgh 4p16.3p16.1 (0–6,531,998 bp)×1, 8p22p21.3 (18,705,388–19,940,445 bp)×3, 10p15.3 (0–1,105,065 bp)×3. Polymorphic DNA marker analysis confirmed a paternal origin of 4p deletion. Prenatal ultrasound revealed facial dysmorphism and hypospadias. The aCGH analysis of the parents revealed no genomic imbalance. Fluorescence in situ hybridization study showed an unbalanced reciprocal translocation between chromosomes 4 and 10 at bands 4p16.1 and 10p15.3. The cytogenetic result, thus, was 46,XY,der(4)t(4;10)(p16.1;p15.3),dup(8)(p21.3p22). The parents elected to terminate the pregnancy, and a 470-g malformed fetus was delivered.ConclusionThe present case provides evidence that an apparently pure 4p deletion can be associated with subtle chromosome imbalances in other chromosomes.     

Prenatal diagnosis of trisomy 18p and distal 21q22.3 deletion

OBJECTIVES: To present the perinatal findings and molecular cytogenetic analysis of concomitant trisomy 18p (18p11.2-->pter) and distal 21q22.3 deletion. CASE AND METHODS: A 29-year-old woman, gravida 2 para 1, underwent amniocentesis at 17 weeks' gestation because she was a carrier of a balanced reciprocal translocation, 46,XX,t(18;21)(p11.2;q22.3). Cytogenetic analysis of the cultured amniocytes revealed a karyotype of 46,XX,der(21)t(18;21)(p11.2;q22.3). The fetus had a derivative chromosome 21 with an extra short arm of chromosome 18 attached to the terminal region of the long arm of chromosome 21. Level II sonograms did not find prominent structural anomalies. The pregnancy was terminated subsequently. At autopsy, the proband displayed a mild phenotype of hypertelorism, a small mouth, micrognathia, a narrowly arched palate, low-set ears, and clinodactyly. The brain and other organs were unremarkable. Genetic marker analysis showed a distal deletion at 21q22.3 and a breakpoint between D21S53 (present) and D21S212 (absent), centromeric to the known holoprosencephaly (HPE) minimal critical region D21S113-21qter. CONCLUSION: Genetic marker analysis helps in delineating the region of deletion in prenatally detected unbalanced cryptic translocation. Fetuses with concomitant trisomy 18p and distal 21q22.3 deletion may manifest inapparent phenotypic abnormalities in utero. Haploinsufficiency of the HPE critical region at 21q22.3 may not cause an HPE phenotype.     

Wolf-Hirschhorn syndrome due to a 3:1 segregation of a maternal balanced t(4;15)(p16.3;q11) translocation

The Wolf-Hirschhorn syndrome (WHS) is characterized by severe pre- and postnatal growth retardation, specific pattern of dysmorphisms, and severe developmental delay. These clinical findings are the result of a deletion within the short arm of chromosome 4. Most cases occur de novo and are of paternal origin. Cases due to a balanced translocation are mostly of maternal origin and the deletion of distal 4p, including the WHS critical region, is often combined with a duplication of the other chromosomal segment involved in the rearrangement. Here, we report on a newborn female infant with WHS and pure tertiary monosomy due to a 3:1 segregation of a balanced maternal 4;15 translocation. In this context, importance of fluorescence in situ hybridization (FISH) with specific probes to determine the exact breakpoints in unbalanced chromosomal rearrangements with breakpoints localized around known microdeletion syndromes is emphasized.     

Prenatal foetal diagnosis of partial trisomy 3q and monosomy 13p due to a maternal balanced rearrangement

The authors describe a case of a male foetus whose ultrasound at 20 weeks' gestation revealed cystic hygroma, cleft lip and ventricular septal defect. Amniotic fluid cytogenetics using GTG banding showed a 46,XY,der(13)t(3;13)(q12;p11.1) rearrangement, and fluorescence in situ hybridization (FISH) delineated the relevant breakpoints. Familial studies identified a maternal balanced translocation involving chromosomes 3 and 13. The post-mortem examination confirmed the prenatal ultrasound findings.     

Prenatal diagnosis of a fetus with a cryptic translocation 4p;18p and Wolf-Hirschhorn syndrome (WHS)

Wolf-Hirschhorn Syndrome (WHS) is caused by distal deletion of the short arm of chromosome 4 and is characterized by growth deficiency, mental retardation, a distinctive, 'greek-helmet' facial appearance, microcephaly, ear lobe anomalies, and sacral dimples. We report a family with a balanced chromosomal translocation 4;18(p15.32;p11.21) in the father and an unbalanced translocation resulting in partial monosomy 4 and partial trisomy 18 in one living boy and a prenatally diagnosed male fetus. Both showed abnormalities consistent with WHS and had in addition aplasia of one umbilical artery. Karyotyping of another stillborn fetus revealed a supernumerary derivative chromosome der(18)t(4;18)(p15.32;p11.21) of paternal origin and two normal chromosomes 4. The umbilical cord had three normal vessels. A third stillborn fetus with the same balanced translocation as the father had a single umbilical artery and hygroma colli.     

Prenatal diagnosis of microdeletion 16p13.11 combination with partial monosomy of 2q37.1-qter and partial trisomy of 7p15.3-pter in a fetus with bilateral ventriculomegaly, agenesis of corpus callosum, and polydactyly

ObjectiveTo present a prenatal diagnosis of microdeletion 16p13.11 with partial monosomy of 2q37.1-qter and partial trisomy of 7p15.3-pter in a fetus with bilateral ventriculomegaly, agenesis of corpus callosum, and polydactyly.Case ReportA 41-year-old well-being Taiwanese, nulligravida woman received amniocentesis at a gestational age of 18 weeks for advanced maternal age. The fetus' karyotype showed 46,XY,der(2)t(2;7)(q36.2;p15.1). Both parents also received cytogenetic examinations and the mother's karyotype revealed 46,XX,t(2;7)(2q36.2;p15.1). High-resolution ultrasound showed the fetus had bilateral ventriculomegaly, agenesis of corpus callosum, and polydactyly of the right hand. After the termination of this pregnancy, the whole genome oligonucleotide-base array comparative genomic hybridization (CGH) by using fetal skin cells demonstrated a 8.44-Mb deletion at 2q37.1 (234602276-243041305), a 22.8-Mb duplication (65558-22869338) at 7p15.3, and an additional 1.32-Mb deletion (14968855-16292235) at 16p13.11.ConclusionArray CGH is a useful tool not only to discover the genomic imbalance at the breakpoints as well as to detect unexpectedly complex rearrangements in other chromosomes. Our case also provided evidence that genomic aberration at chromosome 16p13.11 involves in the formation of polydactyly.     

妇产科疾病与染色体结构畸变重排断裂点分布的研究(附142例报告)

目的：探讨与妇产科相关染色体疾病的染色体平衡结构畸变重排断裂声、分布规律及可能机制。方法：对妇产科疾病142例检出的染色体平衡结构畸变重排断裂点在各染色体、不同类型G带和脆性位卢、上的分布频率与预期值（EV）进行比较。结果：重排断裂除较多累及近端着丝粒染色体外，7、8号染色体受累频率显著性偏高。2、4、5、6号染色体不仅断裂点的分布频率显著性偏低，且有关平衡结构畸变个体的表型异常率显著性增高。重排断裂在G阴性带分布较多，在G阳性带较少，在脆性位点与EV差异无显著性。结论：与妇产科相关的染色体疾病平衡结构畸变的重排断裂声、在不同染色体，不同G显带上的分布是非随机的，其机理既涉及染色体的内在分子生物学特征，也与选择作用相联系。     

Concomitance of 47,XXY,a balanced reciprocal translocation of t(4;17)(q12;q11.2) encompassing SPINK2 at 4q12 and NOS at 17q11.2 and an AZFa sY86 deletion in an infertile male

ObjectiveWe present an infertile male who was incidentally detected to have Klinefelter syndrome, a balanced reciprocal translocation of t(4; 17) (q12; q11.2) and an AZFa sY86 deletion. We review the literature and discuss the significance of 47,XXY, t(4; 17) (q12; q11.2) and AZFa sY86 deletion in this case.Case reportA 37-year-old married infertile male was referred for genetic studies of azoospermia. His height was 195 cm and his weight was 85 kg. He had been married for more than one year without any pregnancy in his wife. He was referred for genetic counseling. Cytogenetic analysis revealed a karyotype of 47,XXY,t(4; 17) (q12; q11.2). In addition to Klinefelter syndrome, a balanced reciprocal translocation and an AZFa microdeletion were found. Sequence analysis of SPINK2 and NOS was also performed. These two fertile related genes were located at the breakpoints of translocation respectively. Heterozygosity of single-nucleotide polymorphisms (SNPs) evidenced the presence of two alleles as well as no deletions occurred at the breakpoint regions. An AZF gene analysis revealed a microdeletion at the region of AZFa sY86 region.ConclusionGenetic analysis of an infertile male may detect multiple factors associated with azoospermia such as translocation, an AZF deletion and Klinefelter syndrome. This case emphasized the importance of tests for chromosomes and AZF deletions among patients with azoospermia. Complete genetic counseling of the consequence of a familial inheritance is also necessary to detect more family carrier members for the prevention of unbalanced chromosome in the offspring.     

A family study of complex chromosome rearrangement involving chromosomes 1, 8, and 11 and its reproductive consequences

Complex chromosome translocations are structural chromosomal rearrangements involving three or more chromosomes and more than two breakpoints. A complex chromosome rearrangement was detected in a phenotypically normal female patient that was referred to the hospital for genetic counseling due to reproductive failure. A cytogenetic evaluation was performed, according to standard method of chromosomal analysis, using G-banding technique. The patient’s karyotype showed a balanced complex chromosome rearrangement (BCCR) involving chromosomes 1, 8, and 11 with three breakpoints 1p31, 8q13, and 11q23. The karyotype designed according to ISCN (2013), is 46,XX,t(1;8;11)(p31;q13;q23) (8qter→8q13::1p31→1qter;8pter→8q13::11q23→11qter;11pter→11q23::1p31→1pter). Additionally, the proband’s mother and brother were tested, resulting in the same exact translocation. In this study, we describe all possible meiotic segregations regarding this translocation, as well as the clinical phenotypes which could arise, if unbalanced products of conception survive. This is a rare case of familial complex chromosome rearrangement, giving a view for its reproductive consequences.