Unbalanced translocation 6p/16q (partial monosomy 6p and trisomy 16q): prenatal diagnosis and cytogenetics

Unbalanced translocation 6p/16q in one fetus is a very rare event and the prenatal sonographic findings have never been published before. We will give a short overview of the literature along with a case report focussing on prenatal ultrasound features and molecular cytogenetic analysis.     

Perinatal findings and molecular cytogenetic analysis of trisomy 16q and 22q13.3 deletion

OBJECTIVES: To present the perinatal findings and molecular cytogenetic analysis of a case with concomitant trisomy 16q and 22q13.3 deletion of paternal origin. CASE AND METHODS: A 24-year-old pregnant woman was referred at 30 weeks' gestation for suspected fetal abnormalities. Sonographic examination revealed decreased fetal movement, dolicocephaly, an asymmetric skull, and intrauterine growth restriction. Prenatal karyotyping was suggested but was declined. A female baby was delivered vaginally at 39 weeks' gestation with a body weight of 2180 g. The neonate presented generalized hypotonia with frequent apneic episodes and died at 1.5 months of age. Additional physical abnormalities included epicanthal folds, ptosis, frontal bossing with an enlarged metopic suture, bitemporal narrowing, hypertelorism, epicanthal folds, a pointed chin, micrognathia, prominent ears with preauricular pits, and clinodactyly. The karyotype from peripheral blood lymphocytes was 46,XX,der(22)t(16;22)(q12.1;q13.3)pat. The microdeletion at 22q13.3 was investigated by fluorescent in situ hybridization (FISH) analysis using the LSI DiGeorge/VCFS region/ARSA dual color DNA probe and the 22q telomeric probe, of which only the latter was able to detect the subtle deletion. Molecular analysis using polymorphic microsatellite markers indicated that the breakpoint at 22q13.31 was located between loci D22S1171 (present) and D22S1168 (absent). CONCLUSION: The use of LSI DiGeorge/VCFS region/ARSA dual color DNA probes to examine distal 22q would miss some subtle terminal deletions of 22q13. However, the use of 22q telomeric probes would detect these minute deletions. Fetuses having trisomy 16q and 22q13.3 deletion may prenatally manifest decreased fetal movement, dolicocephaly, an asymmetric skull, and intrauterine growth restriction and postnatally present generalized hypotonia with frequent apneic episodes.     

Patient with novel interstitial deletion of chromosome 3q13.1q13.3 and agenesis of the corpus callosum

Interstitial deletions of the proximal long arm of chromosome 3 are rare. Only eight previously reported patients have deletions involving the proximal segment of 3q. Of these patients, three had agenesis of the corpus callosum and one had holoprosencephaly. We report here a patient with a small unique interstitial deletion of the long arm of chromosome 3 spanning 3q13.1q13.3. This patient has agenesis of the corpus callosum, global developmental delay, and distinctive facial features of a small nose, anteverted nares, and broad nasal root. Our patient provides further evidence that a gene involved in corpus callosum development or neuronal migration may reside in this region.     

Prenatal diagnosis and molecular cytogenetic characterization of de novo distal 5p deletion and distal 22q duplication

ObjectiveWe present prenatal diagnosis and molecular cytogenetic characterization of de novo distal 5p deletion and distal 22q duplication.Case reportA 34-year-old woman was underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a derivative chromosome 5 [der(5)] with an abnormal distal 5p segment of unknown origin. The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) analysis was performed on the cultured amniocytes, and the result was arr 5p15.33p13.3 (22,149–29,760,922) × 1.0, arr 22q13.2q13.33 (42, 192, 065–51,178,264) × 3.0 [GRCh37 (hg19)] with a 29.739-Mb deletion of 5p15.33-p13.3 encompassing 55 [Online Mendelian Inheritance in Man (OMIM)] genes including TPPP, TERT, SRD5A1, SEMA5A and CTNND2, and an 8.986-Mb duplication of 22q13.2-q13.33 encompassing 82 OMIM genes including TRMU, SCO2, TYMP, CPT1B and SHANK3. The fetal karyotype was 46,XY,der(5)t(5; 22)(p13.3; q13.2)dn. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. Postnatal polymorphic DNA marker analysis confirmed a maternal origin of the aberrant chromosome 5.ConclusionaCGH and polymorphic DNA marker analyses can determine the nature and parental origin of the de novo chromosome aberration, and the information acquired is useful for genetic counseling.     

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.     

5p15缺失综合征合并4q32重复1例临床分析与基因诊断

目的 探讨5p15缺失综合征合并4q32重复的临床特征及分子遗传学特点.方法 回顾分析1例5p15缺失综合征合并4q32重复患儿的临床资料以及分子遗传学分析资料.结果 10月龄女性患儿,具有特殊面容、发育迟缓、先天性心脏病及喉软骨发育不良等临床表现.全外显子测序和染色体组拷贝数分析精确定位拷贝数异常改变的染色体片段区域...     

Large interstitial deletion of chromosome 13q and severe short stature: clinical report and review of the literature

We report a 16 year old African American female with an interstitial deletion of chromosome 13 comprising approximately 40% of the long arm of this chromosome [karyotype 46,XX, del(13)(q14.12q31.2)]. We believe that this case is interesting because of the large size of the chromosome deletion, the severe growth retardation seen in the proband and her prolonged survival.     

Interstitial deletion 13q31 associated with normal phenotype: cytogenetic study of a family with concomitant segregation of reciprocal translocation and interstitial deletion.

Gain or loss of a fragment in human chromosomes has been associated with abnormal phenotypes in numerous genetic disorders. However, it is also possible that lack or excess of a particular chromosomal segment is a neutral polymorphism among populations and thus does not cause obvious abnormal phenotype. In this study, conventional GTG-banded karyotyping and molecular cytogenetic analyses (including fluorescence in situ hybridization, spectral karyotyping and comparative genomic hybridization) were applied to study the genotype-phenotype correlation in a Taiwanese family, in which a concomitant segregation of del(13)(q31q31) interstitial deletion and t(13;18)(q32;p11.2) reciprocal translocation in a 2-year-old girl (the proband) was noticed. Two family members (the father and grandmother of the proband) who carried the del(13)(q31q31) but not the translocation t(13;18) both revealed a normal phenotype at adulthood. The finding, which appears novel, that interstitial deletion 13q31 could be associated with a normal phenotype, is therefore valuable in genetic counseling.     

Prenatal diagnosis of 2q32 deletion syndrome characterized by multiple segmental deletions and complex chromosomal rearrangement involving chromosomes 2, 5 and 7

This is the first case of 2q32 microdeletion syndrome diagnosed prenatally and followed throughout the pregnancy. The pregnancy was complicated by fetal club feet, ventriculomegaly, intrauterine growth retardation and polyhydramnios. This is a unique and highly complicated prenatal diagnosis case of a de novo complex chromosomal rearrangement involving chromosomes 2, 5 and 7 with 15 breaks and multiple interstitial 2q deletions, resulting in the 2q32 microdeletion syndrome. The delineation of the karyotype in this case and origin of the pathology required the use of multiple genetic technologies including conventional cytogenetics, fluorescence in situ hybridization, single-nucleotide polymorphism array and array comparative genomic hybridization.     

Molecular characterisation of a prenatally diagnosed 5q15q21.3 deletion and review of the literature

BACKGROUND: Ultrasound examination performed on a 32-year old woman at 30 weeks' gestation showed the presence of fetal malformations. Amniocentesis was performed. METHODS AND RESULTS: Cytogenetic analysis of cultured amniocytes revealed an interstitial deletion of the long arm of chromosome 5. Molecular studies confirmed that the deletion included the 5q15-21.3 region and was 14 Mb in size. Therefore, the karyotype was: 46,XY,del(5)(q15q21.3). In addition, analysis of polymorphic DNA markers showed that the deletion was of paternal origin. CONCLUSIONS: The pregnancy was terminated at 34 weeks' gestation. At autopsy, the fetus displayed dysmorphic features, thin limbs and renal abnormalities. The clinical findings observed in the fetus as well as in 20 cases reported previously allowed us to further delineate the phenotype of such interstitial 5q15q21.3 deletions.     

Investigation of loss of heterozygosity at specific loci on chromosomes 3p, 6q, 11p, 17p and 17q in ovarian cancer

In an attempt to further define the genetic events in the pathogenesis and progression of human ovarian cancer, an analysis of constitutional and ovarian carcinoma DNA samples revealed loss of heterozygosity (LOH) at specific loci on chromosomes 3p (38%), 6q (23%), 11p (33%), 17p (82%) and 17q (62%). In contrast, LOH was not observed in benign or borderline tumors. No significant association could be demonstrated between LOH at the loci studied and tumor stage, histologic subtype, grade or patient outcome. Further analyses of large tumor panels are now required to determine the relationship between LOH at these loci and the clinicopathological behavior of ovarian tumors.     

Prenatal diagnosis of de novo interstitial 2q14.2-2q21.3 deletion assisted by array-based comparative genomic hybridization: a case report

BACKGROUND: During conventional karyotyping, it can be difficult to clearly identify de novo interstitial deletion of a chromosomal band when there are similar bands nearby. CASE: A 38-year-old, pregnant woman underwent genetic amniocentesis at 18 weeks of gestation due to advanced maternal age. Chromosomal studies detected an interstitial deletion at the long arm of 1 chromosome 2. Array-based comparative genomic hybridization further located the deletion in the band of interstitial 2q14.2-2q21.3. Prenatal ultrasound revealed borderline ventriculomegaly without additional abnormalities of the cardiovascular, urinary or gastrointestinal systems or the spine. Fetal magnetic resonance imaging identified mild dilatation of the posterior horns of the lateral ventricles. At 5 months after birth, the infant had febrile convulsions that were well controlled with medication. A single incisor was noted at 1 year of age. Atrophy of the left, undescended testis and developmental delay were also noted. CONCLUSION: Array-based comparative genomic hybridization is helpful in prenatal diagnosis because it can precisely locate the chromosome bands with copy number changes. Clinical manifestations in this case provide valuable information for genetic counseling pregnant women who conceive a fetus with deletion of interstitial 2q14.2-2q21.3.     

Perinatal findings and molecular cytogenetic analyses of de novo interstitial deletion of 9q (9q22.3-->q31.3) associated with Gorlin syndrome

OBJECTIVES: To present the perinatal findings and the molecular cytogenetic analyses of a de novo interstitial deletion of 9q (9q22.3-->q31.3) associated with Gorlin syndrome. METHODS: Amniocentesis was performed at 18 weeks' gestation on a 27-year-old woman at a community hospital because of a high Down syndrome risk of 1/178, a low maternal serum alpha-fetoprotein (MSAFP) level of 0.66 multiples of the median (MoM), and a high maternal serum human chorionic gonadotrophin (MShCG) level of 3.13 MoM. The karyotype was initially determined to be 46,XY. However, fetal macrocephaly and overgrowth were found at 30 weeks' gestation. Postnatally, the infant manifested characteristic features of Gorlin syndrome. High-resolution chromosomal bandings of the peripheral blood lymphocytes, polymorphic DNA marker analysis to determine the parental origin of the deletion, array comparative genomic hybridization (CGH) to determine the extent of the chromosomal deletion, and fluorescence in situ hybridization (FISH) to determine the deletion of the PTCH gene were performed. RESULTS: The 850-band level of resolution showed an interstitial deletion of 9q (9q22.3-->q31.3). The parental karyotypes were normal. The karyotype of the proband was 46,XY,del(9)(q22.3q31.3)de novo. Polymorphic DNA marker analysis revealed that the deletion was of paternal origin. Array CGH revealed that the deleted region was about 12 Mb, encompassing the segment from 9q22.32 to 9q31.3. FISH analysis using the BAC probe RP11-34D4 and the probe RP11-43505 indicated the deletion of the PTCH gene. CONCLUSIONS: Fetuses with an interstitial deletion of 9q (9q22.3-->q31.3) may be associated with a low level of MSAFP and a high level of MShCG in the second trimester, and sonographic findings of overgrowth and macrocephaly in the third trimester.     

Umbilical cord ulceration after prenatal diagnosis of duodenal atresia with interstitial deletion of chromosome 13q: a case report

Umbilical cord ulceration complicated by massive local hemorrhage may be a lethal event in the fetus, and this ulceration has been reported to be associated with upper intestinal atresia. The diagnosis of umbilical cord bleeding is difficult. We present a case of umbilical cord ulceration, hemorrhage, and duodenal atresia which had, in addition, an interstitial deletion of chromosome 13q. A female infant weighing 1,691 g was delivered by cesarean section at 34 weeks of gestation and had resuscitation and laparotomy. Just before the cesarean section, ultrasonography showed a 'double bubble' sign and a linear shadow, suggesting fibrin in the amniotic cavity. This finding may help in the diagnosis of bleeding from the cord.     

Increased nuchal translucency and split-hand/foot malformation in a fetus with an interstitial deletion of chromosome 2q that removes the SHFM5 locus

OBJECTIVES: To describe and discuss the clinical, cytogenetic and molecular findings in a fetus with the first prenatally detected interstitial deletion of chromosome 2q. CASE REPORT: A fetus with increased nuchal translucency on routine ultrasound examination at 13 weeks' gestation was found to have severe upper-limb abnormalities on follow-up ultrasound examination at 16 weeks. The pregnancy was terminated, and the autopsy revealed monodactyly of the right upper limb, oligodactyly of the left upper limb and bilateral split foot, as well as atrial and ventricular septal defects and mild facial dysmorphism. RESULTS: Cytogenetic studies and haplotype analysis of the fetus and both parents showed that the fetus carried a de novo deletion encompassing a region of about 30 Mb on the paternal chromosome 2q (karyotype 46,XX,del(2)(q24.2-q32.2)). CONCLUSION: This is the first instance of increased nuchal translucency associated with a chromosome 2q deletion. Moreover, the striking malformations affecting all four of the fetus' limbs support previous suggestions that a novel locus for split-hand/foot malformation (SHFM5) lies on chromosome 2q31.     

Interstitial deletions without phenotypic effect: prenatal diagnosis of a new family and brief review

A 39-year-old woman (G4P1SAB2) was referred for amniocentesis for advanced maternal age. An interstitial deletion of the G-dark band 11p12 was found in the fetus. Blood from the mother and her previous son was cultured and the same deletion was found in both. The absence of phenotypic effect in this family further confirms that G-dark euchromatic deletions are compatible with a normal phenotype, and underlines the importance of checking familial karyotypes even when apparently unbalanced structural rearrangements are found at prenatal diagnosis.     

Tall stature and minor facial dysmorphisms in a patient with a 17.5 Mb interstitial deletion of chromosome 13 (q14.3q21.33): clinical report and review

We present a 4-year-old boy with developmental delay and several into minor dysmorphic features due to an interstitial deletion of 17.5 Mb on the long arm of chromosome 13 [46,XY,del (13)(q14.3q21.33)]. The deletion was detected initially during routine cytogenetic screening and further analyzed on a genome-wide BAC array. In contrast to several previous papers reporting a short stature, our patient was tall with a 1 year advanced skeletal age. In this paper, we compare growth and clinical features of this patient with previously reported cases, with a similar interstitial deletion on the long arm of chromosome 13.