A de novo subtelomeric monosomy 11q (11q24.2-qter) and trisomy 20q (20q13.3-qter) in a girl with findings compatible with Jacobsen syndrome: case report and review

We report on a 2-year-old dysmorphic girl with prenatal and postnatal growth deficiency, cardiopathy, left-sided hydronephrosis due to pyelourethral junction stenosis, frequent respiratory infections and psychomotor retardation, in whom a de novo unbalanced submicroscopic translocation (11q;20q) was detected by subtelomeric multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analyses. Additional fluorescence in situ hybridization studies with locus-specific BAC probes and analyses with microsatellite markers revealed that this translocation resulted in a paternal chromosome 11q terminal deletion of approximately 8.9 Mb and a subtelomeric 20q duplication of approximately 3.7 Mb. A subtelomeric 20q trisomy has only been reported in four cases so far. A subtelomeric 11q deletion has been clinically reported in 18 patients. We review the clinical phenotype of these patients. We suggest that patients with a subterminal (11q24.2/25-qter) deletion may present with features of the well-known phenotype of terminal 11q deletion or Jacobsen syndrome.     

Terminal 14q deletion with unbalanced t(Y;14)(q12;q32) translocation

Terminal deletions of chromosome 14q are very rarely reported. Schneider et al. (2008) reviewed about 20 cases of 14q32 region deletion in a previous article and only three of the cases involved autosomal translocations; however, no sex chromosome translocations were reported. Here we report the clinical findings of a patient with terminal 14q32 deletion derivated from at (Y;14)(q12;q32) translocation.     

Prenatal findings and molecular cytogenetic analyses of partial trisomy 12q (12q24.32-->qter) and partial monosomy 21q (21q22.2-->qter)

OBJECTIVES: To present the prenatal findings and molecular cytogenetic analyses of partial trisomy 12q and partial monosomy 21q, and a review of the literature. METHODS: Amniocentesis was performed at 23 gestational weeks in a 33-year-old woman because of abnormal sonographic findings. Amniocentesis revealed a derivative chromosome 21, or der(21), with a deletion on the region of 21q22.2 and an addendum of a small chromosomal segment of unknown origin. The maternal karyotype was subsequently found to be 46,XX,t(12;21)(q24.32;q22.2). Level II ultrasound showed microcephaly, micrognathia, a ventricular septal defect, and rocker-bottom feet. The pregnancy was terminated. A malformed infant was delivered without the phenotype of holoprosencephaly (HPE). Fluorescence in situ hybridization (FISH) and polymorphic DNA markers were used to investigate the involved chromosomal segments. RESULTS: FISH study showed the absence of the signal of 21q subtelomeric probe and the presence of the signal of 12q subtelomeric probe in the der(21).The fetal karyotype was 46,XY,der(21) t(12;21)(q24.32;q22.2)mat. Genetic marker analysis showed a deletion at 21q22.2 and a breakpoint between D21S156 (present) and D21S1245 (absent). The deleted segment was measured about 4.5 Mb encompassing the HPE critical region. CONCLUSIONS: Molecular genetic analyses help in determining the prenatally detected unbalanced cryptic translocation as well as parental balanced subtle translocation. A duplication of 12q24.32-->qter and a deletion of 21q22.2-->qter may be associated with prenatal sonographic findings of microcephaly, borderline ventriculomegaly and cerebellar hypoplasia, micrognathia, a ventricular septal defect, and rocker-bottom feet. Haploinsufficiency of the HPE critical region at 21q22.3 may not cause an HPE phenotype.     

A patient with a de novo t (6;9) and an interstitial duplication of (9)(q21.2q22.1).

We report on a 4-year-old child with psychomotor retardation, general hypotonia and only mild dysmorphic features. Her chromosome constitution was 46,XX, t (6;9) (q27;q22.1), dup (9) (q21.2q22.1). This de novo interstitial duplication was confirmed using fluorescence in situ hybridisation (FISH) with band-specific probes. This is the second report of a patient with an interstitial duplication of this region of the long arm of chromosome 9. It is concluded that in a child with an abnormal phenotype and a de novo (apparently) balanced translocation, the possibility of a small duplication or deletion should be considered.     

Mild dysmorphic signs in two male sibs with partial trisomy 2q32.1-->q35 due to maternal ins(14;2) translocation.

We report two male sibs with minor congenital anomalies and moderate to severe developmental delay who are trisomic for the interstitial 2q32.1-->q35 segment. The partial 2q duplication derived from a maternal balanced insertion translocation, 46,XX,dir ins (14;2)(q22;q32.1q35). To the best of our knowledge, no similar case observation has been previously published.     

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.     

Male factor infertility associated with a familial translocation t(1;13)(q24;q10)

We report a case of a family with one sister and one brother in which the brother inherited a t(1;13)(q24;q10) translocation from his mother. We describe a case with a clear translocation between the long arm of chromosome 1 and the long arm of chromosome 13. It is possible that the APOE and MTHFR genotypes and lower folate status may also be responsible for the above mentioned translocation.     

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.     

Prenatal diagnosis of monosomy 4p14-->pter and trisomy 11q25-->qter: clinical presentations and outcomes

We present the case of a pregnant woman with low free beta-HCG in maternal serum Down syndrome screening that led to prenatal diagnosis of a fetus with 46,XY,der(4)t(4;11)(p14; q25). This chromosomal aneuploidy resulted from unbalanced segregation of a paternal balanced translocation, t(4;11)(p14;q25). Prenatal ultrasound revealed intrauterine growth restriction, cleft lip and palate, a thick nuchal fold, a single umbilical artery, and pyelectasis. Array-based comparative genomic hybridization and short tandem repeat markers further located the exact breakpoint of translocation. The woman had her pregnancy terminated at 23 weeks of gestational age. The proband had general appearance of Wolf-Hirschhorn syndrome and some unique findings, including single umbilical artery, severe immunoglobulin deficiency, scalp defect, and underlying bony defect. Our case underscores the importance of fetal karyotyping when low maternal serum free beta-HCG is found. It also adds information on the fetal presentations of monosomy 4p14-->pter and trisomy 11q25-->qter.     

Prenatal detection of deletion 6q13q15 in a complex karyotype

OBJECTIVES: Prenatal diagnosis of a pregnancy with elevated maternal serum alpha-fetoprotein identified a karyotype with a complex chromosomal rearrangement, a Robertsonian translocation and a 6q deletion involving bands q13q15. Sonography identified mild IUGR, polyhydramnios and micrognathia. The infant presented with multiple congenital anomalies, primarily limited to the head and neck, including hypertelorism, broad nose, micrognathia, cleft palate, microglossia and low-set ears with microtia. METHODS: Amniocytes of the fetus and blood of the patient and her parents were analyzed by cytogenetics and fluorescence in situ hybridization. RESULTS: The karyotype on the fetus was 45,XX,t(3;21;20)(p12;q11.2;p11.2), del(6)(q13q15),der(13;14) (q10;q10)mat. CONCLUSION: The 13;14 Robertsonian translocation was inherited from the mother and the three-way translocation appeared to be balanced. The patient had facial dysmorphology similar to that which has been described in 6 previously reported cases with the same deletion involving 6q13q15. There was no recognizable abnormality of limbs or digits, and the autopsy did not identify defects involving the internal organs.     

Female pseudohermaphroditism in a fetus with a deletion 9(q22.2q31.1)

Interstitial deletions of chromosomal region 9q are rarely seen. We report the first prenatal diagnosis of a de novo interstitial deletion 9q. The fetus was karyotyped for intrauterine growth retardation (IUGR). Conventional and molecular cytogenetics showed female karyotype with a de novo deletion of the chromosomal region 9(q22.2q31.1) leading to a partial monosomy 9q. At autopsy, the fetus showed growth retardation, dysmorphy, and a female pseudohermaphroditism. These results suggest that a gene(s) for genital development reside in chromosomal region 9q22.2q31.1.     

Six cases of deletion 9p24 and trisomy 19q13.4 inherited from a familial balanced translocation.

The deletion 9p with trisomy 19q syndrome is a rare disorder. We report 2 adults and 4 children with deletion 9p and trisomy 19q due to familial balanced 9p;19q translocation with clinical features suggestive of monosomy 9p. The children had dysmorphic features and psychomotor retardation while the adults were self-sufficient but worked in a sheltered environment. High-resolution chromosome analysis and fluorescence in situ hybridization confirmed that the 6 cases of unbalanced translocation, der(9)t(9;19)(p24.1;q13.4) were inherited from a balanced translocation carrier, t(9;19)(p24.1;q13.4). The dysmorphic features included trigonocephaly, small nose with stunted tip, and long philtrum. Associated anomalies included wide-set nipples, extra finger flexion creases, hernia, external genitalia hypoplasia, scoliosis, and hypopigmented skin patch. We suggest that genetic counseling is necessary for those who have family members with dysmorphic features and/or major anomalies and/or psychomotor retardation.     

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.     

Syndromic encephalocele in a fetal case with a 1p35-pter deletion and a 14q32-qter duplication inherited from a maternal balanced translocation

Occipital encephalocele belongs to the family of neural tube defects, which occur in one among 2000 to 5000 live births. Syndromic encephaloceles include Meckel-Gruber syndrome and various chromosomal abnormalities. We report on a fetal case (13 WG) with bilateral cleft lip and palate, choanal atresia, occipital encephalocele, bilateral club feet, bilateral multicystic kidneys, enlarged bladder and urethral atresia. The fetal chromosome analysis showed a maternally inherited unbalanced translocation between the short arm of chromosome 1 and the long arm of chromosome 14, resulting in 1p35-pter deletion and 14q32-qter duplication (46,XY,der(1),t(1;14)(p35;q32)). Since the chromosomal breakpoints have not previously been implicated in syndromic encephalocele, this observation is of interest for the identification of other genes responsible for occipital encephalocele.     

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.     

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.     

Interstitial deletion of chromosome 14q in a Taiwanese infant with microcephaly.

Deletion (14)(q11.2q13.1) is a rare cytogenetic abnormality associated with severe neurological deficit, microcephaly and psychomotor retardation. We report a case of de novo interstitial deletion of chromosome (14)(q11.2q13.1) in an 8-month-old girl, who presented with marked microcephaly, a nearly closed anterior fontanelle, dysmorphic facies, severe neurological deficits, and delayed developmental milestones. Three-dimensional computed tomography of the brain showed premature closure of the coronal suture and magnetic resonance imaging of the brain showed frontal atrophy and hypoplastic corpus callosum.     

Molecular cytogenetic analysis and clinical findings in a newborn with prenatally diagnosed rec(7)dup(7q)inv(7)(p22q31.3)pat

We report prenatal and early postnatal findings in a newborn with a partial trisomy of chromosome 7 (7q31.3-qter), arising from meiotic recombination of a paternal pericentric inversion, inv(7)(p22q31.3). The inversion breakpoints were localized and the regions of duplication and deletion were defined by fluorescence in situ hybridization (FISH) analysis using a series of locus-specific and subtelomeric probes. To our knowledge, only three cases involving a recombinant 7 with duplication of 7q have been reported, two of these being first cousins. The clinical findings in our patient included skeletal abnormalities, facial dysmorphism, dilated cerebral ventricles, microretrognathia and short neck. These findings and some aspects of the neonatal course were consistent with the phenotype previously reported for duplication of distal 7q, without associated monosomy for sequences from another chromosome.     

Clinical significance of 45XX, t(13q14Q) Robertsonian translocation: unexpected triploidy in third abortion of female carrier

A case report is described of a female t(13q14q) Robertsonian translocation carrier. Her firstborn daughter appeared to be a carrier of the same translocation. Chromosomal investigation of the third of three subsequent spontaneous abortions revealed a triploidy (69XXX). Literature shows discrepancies in the reported abortion rate in the reproductive performance of t(13q14q) carriers. It is concluded that these could in part be explained by heterogenicity of the study groups due to variable presence of other factors known to influence the abortion risk. In our case report treatment for epilepsy, a luteal phase defect and high numbers of spermatozoa in the sperm count of the husband must be considered as contributory factors. It is recommended to perform systematic investigations in all cases of recurrent abortion even when a chromosomal anomaly is found in one of the partners.     

Genetic risk of families with t(1;2)(q42;q33) GTG, RHG, QFQ, FISH

OBJECTIVES: A central concept in genetic counseling is the estimation of the probability of recurrence of unfavourable pregnancy outcomes (abortion, stillbirth and birth at malformed child). In case of chromosomal changes estimates are made on basis of segregation analyses in actual pedigree. If we have a few of pedigree members than risk estimate should be performed on basis combined our data and empiric data from literature. We present individual genetic risk for carriers of unique reciprocal translocation t(1;2)(q42;q33) detected through karyotyping of the patient with miscarriage. MATERIAL AND METHODS: The pedigree consisted 5 families of t(1;2)(q42;q33) carriers with 15 members of progeny was evaluated according to Stene and Stengel-Rutkowski. Cytogenetic analysis of persons of these families (7 persons) was performed on blood samples using GTG, RHG, QFQ and FISH techniques. Additional RCT pedigree analysis of Stengel-Rutkowski et at Collection, Polish Collection, Lituanian Collection, Bielorussian Collection and an available literature cases were performed. RESULTS: The translocation was classified as translocation at risk for double segment imbalances for trisomy 1q42-->qter together with monosomy 2q33-->qter or monosomy 1q42-->qter together with trisomy 2q33-->qter after 2:2 disjunction after adjacent-1 segregation of the meiotic chromosomes. Two improved risk values for RCT with segments 1q42-->qter, 2q33-->qter were obtained i.e. 6/44 (13.6% +/- 5.2%) and 4/20 (20% +/- 8.9%). The probability of occurrence for this translocation carriers was estimated as 7% (medium risk). On basis of direct analysis at presented pedigree a risk for miscarriage was estimated as 2/9. CONCLUSIONS: 1. Carrierships of t(1;2)(q42;q33) increased population risk value for unbalanced progeny at birth by 7% (medium risk) and for miscarriage 2/9. 2. Causative relation between presence of t(1;2)(q42;q33) and miscarriages is suggested. 3. Updated, new genetic risk values for RCT at risk for single segment 1q42-->qter imbalance is 6/44 (13.6% +/- 5.2%) at birth and for single segment 2q33-->qter imbalance is 4/20 (20% +/- 8.9%).