Cryptic translocation t(5;18) in familial mental retardation

A cryptic translocation t(5;18)(qter;qter) was detected in a large family, using a FISH-based approach combining subtelomeric probes to allow the subtelomeric regions of most chromosome ends to be analysed for deletions and balanced or unbalanced translocations. Unbalanced karyotypes (duplication 5qter/deficiency 18qter) resulted in a previously undescribed association of moderate to severe mental retardation, microcephaly, pre- and postnatal growth retardation, distinct facial dysmorphism, narrow auditory canals, genital hypoplasia, left heart hypoplasia in one patient and severe behaviour difficulties in another. Some of the features observed in affected individuals are characteristic of known syndromes involving either 18q (growth deficiency, nystagmus, narrow auditory canals, genital hypoplasia, behaviour problems in 18q deletion syndrome) or 5q (umbilical and inguinal hernias, congenital heart defects in distal 5q trisomy).     

Partial duplication of 17 long arm

Three subjects from 2 unrelated families with partial duplication of 17q, derived from a reciprocal parental translocation between chromosomes 11 and 17 with different breakpoints, are described. A female patient from one family with a 46,XX,-11,+der(11),t(11;17)(q24;q23.2)pat chromosome complement had died at 2 months of age. In the second family, a male propositus and a subsequent fetus, identified by cytogenetic prenatal diagnosis, showed a 46,XY,-11,+der(11),t(11;17)(q2505,q24.3) mat chromosome complement. Twelve other cases involving partial duplication of chromosome 17 have been reported, 11 of these derived from a balanced translocation, and 1 was a duplication. All these cases showed psychomotor and mental retardation, cranial contour anomalies, micrognathia, bulbous nose, short neck, skeletal anomalies, and CNS defects. The phenotypic and clinical observations in the three subjects of this report are compared with previously reported findings.     

Array CGH characterization of an unbalanced X-autosome translocation associated with Xq27.2–qter deletion, 11q24.3–qter duplication and Xq22.3–q27.1 duplication in a girl with primary amenorrhea and mental retardation

We present array comparative genomic hybridization (aCGH) characterization of an unbalanced X-autosome translocation with an Xq interstitial segmental duplication in a 16-year-old girl with primary ovarian failure, mental retardation, attention deficit disorder, learning difficulty and facial dysmorphism. aCGH analysis revealed an Xq27.2–q28 deletion, an 11q24.3–q25 duplication, and an inverted duplication of Xq22.3–q27.1. The karyotype was 46,X,der(X)t(X;11)(q27.2;q24.3) dup(X)(q27.1q22.3). We discuss the genotype–phenotype correlation in this case. Our case provides evidence for an association of primary amenorrhea and mental retardation with concomitant unbalanced X-autosome translocation and X chromosome rearrangement.     

Distal trisomy 14q

Two cases of de novo duplication of the distal part of the long arm of chromosome 14 are reported. In one case, the partial trisomy of 14q is due to translocation of a segment (14q24 to 14qter) at the end of the satellite stalk of chromosome 14. The clinical picture is very severe. In the second case, a tandem duplication in 14 (q23----q32) is present with only minor malformations and mild mental retardation.     

Partial trisomy of the distal part of 10q: a report of two Egyptian cases

Partial trisomy of the distal third of the long arm of chromosome 10 is a well defined but rare syndrome. Most cases result from an unbalanced translocation. Growth retardation, developmental delay and characteristic dysmorphic features are well described in the syndrome. This report includes 2 Egyptian cases with partial 10q trisomy involving different breakpoints. Cases were subjected to full clinical examination and detailed cytogenetic analysis using conventional and FISH studies. Results showed that the karyotype of case 1 was 46,XX,der(7)t(7;10)(p22;q23).ish(wcp7+;wcpl0+) and the karyotype of case 2 was 46,XX,der(7)t(7;10)(p22;q25).ish(wcp7+;wcp 10+). The chromosomal abnormalities in case 1 resulted from a paternal balanced translocation while case 2 resulted from a maternal balanced translocation involving chromosomes 10 and 7 in both cases. The probands' phenotypes were correlated to the breakpoints and compared to previously reported cases with partial trisomy 10q. Both cases had the well characterized phenotype of the distal trisomy of 10q in the form of mental retardation, microcephaly, characteristic dysmorphic facies and limb anomalies as trisomy in both cases involved the 10q25-->qter region. However, case 1 with 10q23-->qter duplication showed more severe clinical manifestations than case 2 with less extensive 10q25-->qter trisomy. These included severe failure to thrive, cardiac involvement and death from respiratory and heart failure. This study confirmed that unbalanced chromosome regions of the long arm of chromosome 10 play an important role in developmental malformations and that a more severe form is associated with involvement of 10q23. It also emphasizes the importance of increasing public awareness regarding these chromosomal rearrangements and the importance of genetic counseling and prenatal diagnosis to avoid recurrences and associated family stress. This was clearly demonstrated in the second family in this study as the couple refused any follow up or further investigations due to religious beliefs despite their social and educational level.     

Interchromosomal insertions

In five families with questionable chromosome rearrangements, we identified an interchromosomal insertion by fluorescent in situ hybridization (FISH). In case 1 with a dir ins (5;11)(p14;q14q24) in three generations, the mentally retarded and microcephalic proband showed a 5p14-->pter deletion. In case 2, a duplication (13)(q21.31--> q31.2) combined with a deletion (11)(q14-->q22) segregated from a reciprocal ins(11;13)(q14q122)(q21.32q31.2), causing a mixed phenotype with psychomotor retardation, caput quadratum, choanal atresia, and pes equinovarus. In case 3, a dir ins (18;5)(q21.3;p13.1p14) was associated with spontaneous abortions, in case 4, the proband with mental retardation, microcephaly, and a heart defect showed a pure trisomy of (12)(q13-->q15), which had segregated from a carrier of an ins (18;12)(p11.3;q13q15). In case 5, a duplication of (10)(q26.3-->q25.2) segregated from an inv ins(5;10)(q15;q26.3q25.2), which was passed on directly from a mother to her son,with mental retardation. In all families the elucidation of the insertional translocation (IT) considerably increased the associated genetic risks of carriers. For the review, we collected data from 81 articles on 87 IT probands on ascertainment, origin, familial transmittance, progeny, and genetic risks of IT carriers. We also discussed the recombinant chromosomes and complex rearrangements associated with ITs, and listed chromosome regions occurring solely as deletions, or solely as duplications, or as both to facilitate genotype/phenotype correlations. We conclude that ITs are rare chromosomal rearrangements with an 1:80,000 incidence, of which nearly 80% were referred because of congenital abnormalities and mental retardation. A maternal origin was seen in 59.5%, a paternal origin in 26.6%, and 13.9% were de novo. No notable difference in fertility between male and female IT carriers was noticed. Bias of ascertainment was excluded in 15 familial cases and led to an estimate of the genetic risks for IT carriers of 32.0-36.0%. The mean size of the inserted regions occurring solely as duplications (n=39) measures 0.96% of the haploid autosomal length (HAL), and of regions solely occurring as deletions (n=14) 0.47% HAL. In the families where both aneusomies occurred, the size of the insertions ranged between 0.22 and 1.21% HAL. Overall, the findings fit with the general idea that a surplus of genetic material is tolerated more easily than a deficiency.     

Pure partial trisomy 5q33-->5q35 resulting from the adjacent-1 segregation of a paternal (5;14)(q33;p12) translocation.

A 14-year-old male was referred for evaluation of mental retardation with short stature and dysmorphic features. His karyotype was 46,XY,der(14)t(5;14)(q33;p12)pat, resulting in a pure partial 5q33-q35 trisomy due to the adjacent-1 segregation of a paternal balanced translocation. Paternal blood karyotype revealed a balanced translocation t(5;14)(q33;p12) retaining Ag-Nors. To date, only two cases of pure partial 5q trisomies spanning this region have been reported. Analysis of these cases and the one we report does not allow the delineation of a specific phenotype.     

Partial duplication of the long arm of chromosome 5: A case due to balanced paternal translocation and review of the literature

Summary A partial duplication of the distal segment of the long arm of chromosome 5 (q31qter) was observed in an infant with congenital malformations and dysmorphic features. The phenotypically normal father had a balanced translocation between the long arm of chromosome 5 and the short arm of chromosome 9: 46,XY,t(5;9)(q31;p24).The clinical and cytogenetic data obtained from six patients with partial duplications of two different long arm segments of chromosome 5 suggest that partial duplication of the distal long arm of chromosome 5 is associated with microcephaly, hypertelorism, epicanthus, strabismus, large upper lip, low-set, dysplastic ears, in addition to growth and psychomotor retardation. Partial duplication of the proximal part of the long arm of chromosome 5, on the other hand, is associated mainly with musculoskeletal abnormalities including muscle hypotrophy and hypotonia, scoliosis, lordosis, pectus carinatum, cubitus valgus, and genu valgum, in addition to psychomotor retardation. The dysmorphic features in this latter group include a bulging forehead, short nose, thick upper lip, low-set protruding ears and tapering, thin fingers.     

Spectral karyotyping and fluorescence in situ hybridization analysis of de novo partial trisomy 7p (7p21.2-->pter) and partial monosomy 12q (12q24.33-->qter)

An 8-year-old boy presenting with hypotonia, moderate mental retardation, developmental delay, and psychomotor retardation is reported. Magnetic resonance imaging of the brain at age 3 years revealed a Dandy-Walker variant. Cytogenetic analysis of the peripheral blood revealed a derivative chromosome 12 with unknown additional material attached to the distal region of the long arm of chromosome 12. The parental karyotypes were normal. Spectral karyotyping (SKY) using the 24-color SKY probes and fluorescence in situ hybridization (FISH) using the specific 7p, 7q, 12p, and 12q telomeric probes confirmed a duplication of distal 7p and a deletion of terminal 12q. The karyotype of the proband was designated as 46,XY.ish der(12)t(7;12) (p21.2;q24. 33)(SKY+, 7pTEL+, 12qTEL-). The present case provides evidence for the association of partial trisomy 7p (7p21.2-->pter) and partial monosomy 12q (12q24.33-->qter) with a cerebellar malformation and the usefulness of SKY and FISH in the identification of a de novo aberrant chromosome resulting from an unbalanced translocation.     

Partial trisomy 10q

Summary Five cases from two nonrelated families with partial trisomy 10q due to a reciprocal translocation t(10;17)(q25;p13) and t(10;11)(q24;q23), respectively, are reported. The phenotypic findings are compared with those of 17 previously published cases; the clinical data justify the conclusion that cases with trisomy 10q show a specific syndrome of mental retardation and malformation characterized by psychomotor retardation, growth retardation, hypotonia, high forehead, flat face, fine and arched eyebrows, antimongoloid slant of the eyes, narrow palpebral fissures, hypertelorism, short nose, bowshaped mouth, short neck, (kypho)scoliosis, and in some cases microcephaly.     

An unusual clinical characterization of a male with distal partial trisomy 1q42.1 and monosomy 4q35.1 and review of the literature

We report a male patient with a karyotype of 46,XY, der(4)t(1;4)(q42.1;q35.1) inherited from a maternal balanced translocation involving chromosome 1q and 4q. The boy had corpus callosum dysgenesis, laryngomalacia, tracheobronchus, facial dysmorphism, simian creases, and developmental retardation. The first three features are unique compared to previous literature reports on distal partial trisomy 1q. This case report allows a further delineation of the distal partial trisomy 1q syndrome.     

Incomplete trisomy 22

Summary Two brothers with duplication of the distal segment of 22q inherited from a t(6;22)(q27;13) translocation carrier mother presented with intraurine growth retardation, congenital hydrocephalus, cleft palate, genital hypoplasia with cryptorchidism and hypospadias, and similar facial features including mongoloid position of eyeaxes, hypertelorism, small nose with prominent bridge, prominent upper lip, and small mandible. In addition the second sib revealed renal hypoplasia, arrhinencephaly and pentalogy of Fallot. The patients died at ages eight days and one day, respectively. The two brothers appear to be the first instances of familial trisomy 22q13qter.     

Partial trisomy 18(q11 leads to qter) in an infant and aborted fetus resulting from a balanced paternal translocation t(13;18)(q32:q11).

Partial trisomy 18 is described in a two month old female with severe mental, motor and growth retardation, associated with multiple congenital anomalies characteristic of complete trisomy 18. Trisomy for almost all of 18q resulted from adjacent I segregation of a paternally inherited translocation t(13; 18)(q32:q11). The balanced translocation was observed in three generations of the family. Partial trisomy 18q identical to that observed in the proband was found in a subsequent miscarriage.     

A duplication dup(4)(q28q35.2) de novo in a newborn

We report here a case of a newborn with hypotrophy and somatic stigmatization: microcephaly, facial dysmorphism, heart defect and immunodeficiency syndrome. The proband's karyotype was 46,XY,dup(4)(q28q35.2) de novo with chromosomal breaks in 4% of metaphases. We demonstrate the usefulness of a combination of physical examination, classical cytogenetics, FISH and PCR techniques in order to establish correct diagnosis because of overlap of some clinical and cytogenetic features of Nijmegen breakage syndrome (NBS) and duplication 4q in our patient. Although FISH technique detected translocation t(14q;21q) in 4 metaphases, deletion 657del5 in exon 6 of the NBS1 gene associated with NBS in Slavic population was not confirmed. We compare in this report similarity of the clinical picture of our patient, NBS cases and other patients carrying a duplication of the distal part of 4q as described in the literature.     

Molecular analysis of a t(7;14)(q35;q32) chromosome translocation in a T cell leukemia of a patient with ataxia telangiectasia

Molecular analysis of somatic cell hybrids derived from T cells carrying a t(7;14)(q35;q32) chromosomal translocation from a patient with ataxia telangiectasia and T cell leukemia indicates that the breakpoint on chromosome 14 is proximal to the IgH locus and to the D14S1 locus, while the breakpoint on chromosome 7 involves the T cell receptor beta chain locus immediately 5' to J beta 1.5 on chromosome 7. The separation of V beta and C beta observed in somatic cell hybrids defined the orientation of the T cell receptor beta chain locus on chromosome 7 where the V beta genes are centromeric and the C beta genes are telomeric. A novel chromosomal alteration, undetected cytogenetically, was revealed as being an inversion with duplication of the distal band of chromosome 14q32. The importance of the 14q32 region in the leukemogenic process is discussed.     

Partial trisomy of chromosome no. 1 in two adult brothers due to maternal translocation (1q-;6p+)

Summary Extra chromosome material on the short arm of chromosome no. 6 (46,XY,6p+) was found in two mentally retarded adult half-brothers with mildly dysmorphic features. The phenotypically normal mother had a balanced translocation between the long arm of chromosome no. 1 and the short arm of chromosome no. 6: 46,XX,t(1;6)(q32;p25). Thus the two affected brothers were trisomic for the long arm segment of chromosome no. 1, distal to q32. These patients, with mildly dysmorphic features and mental retardation, represent the first cases of partial trisomy 1q surviving to adulthood.The clinical and cytogenetic data obtained from eight individuals with partial trisomies for different long arm segments of chromosome no. 1 suggest that partial trisomy of the distal two-thirds of the long arm is characterized by severe malformations, growth retardation, and early death. Conversely, partial trisomy for the distal one-third of the long arm is associated with milder malformations and longer survival time as well as growth and mental retardation.     

Trisomy 20p: case report and genetic review

Partial trisomy for the distal part of the short arm of chromosome 20 reported in a girl aged 11/2 years with typical craniofacial dysmorphies and psychomotor retardation. The trisomy resulted from a paternal translocation t(14;20) (q32.3;p11.1). The review of 25 cases of partial trisomy 20p showed that most cases (22 : 25) were due to parental translocations. Predominant involvement of small chromosomes in translocations with chromosome 20 was also detected.     

Clinical and cytogenetic study of a case with familial chromosomal translocation presenting with facial dysmorphism and axial neuropathy

We report on a 9-year-old female patient presenting with muscle weakness, facial dysmorphism and mild mental retardation. She had low birth weight, developmental delay, hypotonia and hyporeflexia and difficulties in climbing the stairs. EMG revealed axonal polyneuropathy affecting both upper and lower limbs. She was the child of non-consanguineous parents, her cytogenetic findings revealed 46,XX,t(12;14)(q14;q23). The mother's karyotype was normal 46,XX while the father's karyotype was 46,XY,t(12;14)(q14;q23) the same as his daughter. Her normal sister's karyotype was also 46,XX,t(12; 14) (q14;q23). Fluorescence in situ hybridization (FISH) was used to elucidate the breakpoints and Array-CGH was done for the patient to confirm the balanced translocation. This observation is of interest because it represents a rare case of a balanced translocation with abnormal phenotype. Mutant genes causing axonal neuropathy have been located on various chromosomes other than 12q14 or 14q24. This report shows the importance of molecular cytogenetics and its correlation with abnormal phenotype and the possibility of another gene locus at the presently studied chromosomal breakpoints. Detailed correlations between chromosome aberrations and their phenotypes are of invaluable help in localising genes for axonal polyneuropathy.     

A 45,XX,-5,-14,+t(5q;14q)mat cri du chat child.

A two-year-old girl has the following features of the cri du chat syndrome: microcephaly, hypertelorism, downward slanting of the palpebral fissures, psychomotor retardation and a cat-like cry. She is only of five patients having the cat cry syndrome with 45 chromosomes. Her karyotype is 45,XX, -5, -14, +t(5; 14)(5qter leads to 5p11: : 14q11 leads to 14qter) with the translocation inherited from her mother and maternal grandmother, each of whom is the carrier of a balanced translocation 46,XX,t(5;14)(p11q11). Normal plasma activity for hexosaminidase B suggests the locus for this enzyme is not located in the delected segment of 5 p.     

Partial trisomy 15q due to maternal translocation t(7;15)(q35;14)]

Partial trisomy for the long arm of chromosome 15 was detected in a 21-year-old girl with severe growth and mental retardation. A balanced reciprocal translocation - t(7;15)(q35;q14) - is present in the mother.