Segregation of Three Reciprocal Translocations in the Same Family: t(3;4), t(5;10), and t(15;21)

Louise Telvi, Martine Folhen, Odile Raoul, Josué Feingold, Gérard Ponsot, Alain Pompidou, Marie O. Rethore, and Jérôme Lejeune

American journal of Medical Genetics 42:716-719 (1992)


Résumé :

A male infant with static antenatal encephalopathy and epilepsy was found to have a duplication of 5p12 ? 5pter and deficiency of 10p13 ? 10pter. Each of his parents was a carrier of a balanced reciprocal translocation. A third translocation was found in the maternal grandfather. The pedigree of each translocation and the segregation of parental reciprocal translocations are discussed.

Sommaire

Haut

Introudction

The incidence of balanced chromosomal translocations, not including Robertsonian translocations in newborn infants, is between 0.18% [Hook et al., 1989] and 0.29% [Jacobs, 1990]. The chance mating of 2 such carriers and the identification of a carrier of 2 different reciprocal translocations from such a mating is rare. To our knowledge, only 4 cases have been reported [De Grouchy et al., 1972; Mulcahy et al., 1983; Hansen et al., 1983; Neu et al.,1988].

The occurrence of a second reciprocal translocation in the family of one of these carriers has never been reported.

We report on an infant with static antenatal encephalopathy and epilepsy resulting from a chromosomal imbalance inherited from his t(5;10) carrier father. He also carries a t(3;4) balanced translocation inherited from his mother. A carrier with a different translocation t(15;21) was identified in the mother's family.

Haut

Clinical report

The propositus, C.M., was born on December 9,1988, to a 25-year-old gravida 1 woman and her 26-year-old husband. The pregnancy was uneventful. Delivery was at the 39th week of gestation. Birth weight, length, and head circumference were 2930 g, 50 cm, and 34.5 cm, respectively.

The child had profound mental retardation. Physical examination showed a rather distinct appearance (Figs. 1 and 2; Table 1): large face, high and flat forehead, flat nasal bridge, microphthalmia, horizontal palpebral fissures, epicanthus, hypertelorism, large and apparently low-set ears, microretrognathia, and highly arched palate. He also had pyloric stenosis and complications, including a urinary tract infection at 4 days of life and feeding problems throughout the first month of life. Neurologically the child was profoundly hypotonic, with myoclonic seizures treated with carbamazepine and clonazepam without evident success. There was no eye contact. A pyramidal syndrome was present. At 18 months, there was no progress in psychomotor development. He had profound mental retardation and could neither stand nor walk. He died at 20 month. The parents refused autopsy.


Fig. 1. - Patient at 20 months.


Fig. 2. - Profile of patient at 20 months.


Fig. 3. - Chromosome pairs involved in translocations from the propositus (C), mother (A), and father (B). Arrows indicate translocated segments.


Fig. 4. - Pedigree chewing transmission of each translocation through 5 generations.

Haut

Laboratory examination

CT scan and MRI showed partial posterior agenesis of the corpus callosum. Abdominal ultrasound documented normal kidneys, liver, and spleen. The ophthalmoscopic findings were normal. Bone age was normal. The results of routine blood and urine analyses were normal.

Haut

Amino Acid Analysis

Plasma and urine amino acids were studied by chromatography (Pr. P. Kamoun and Dr. D. Rabier, Laboratoire de Biochimie Médicale, Hôpital des Enfants Malades Paris) and were analyzed statistically according to the method of Lejeune et al. [1990]. Performed at 8 months and 20 months of age, respectively, the 2 examinations showed an increase of the relative concentration of glutamate and glutamine. The serum glutamate and glutamine represented 279% of the total amino acids (normal: 208 ± 29), and urinary excretion of glutamate and glutamine represented 156% of the total amino acids (normal: 92 ± 29).

Haut

Cytogenetic Findings

Lymphocytes were cultured according to a standard method. Banding patterns were analyzed using the RHG technique of Dutrillaux et al. [1971] and the RTBG technique of Viegas-Pequignot et al. [1978].

The mother was a balanced carrier of a t(3;4)(p12;p15.1) translocation and the father of a balanced t(5;10)(p12;p13) translocation. The propositus had a 46, XY, t(3;4)(p12;p15.1)mat, -10, + der10t(5;10)(p12p13)pat. karyotype in RHG and RTBG banded studies from peripheral blood cultures (Fig. 8). Thus, the patient has a dup(5)(p12 -> 5pter) and del(10)(p13 10pter). In the mother's family we found a third translocation t(15;21) (q26.2;q21), which was published by Raoul et al. [1976]. The pedigree shows the segregation of each of 3 translocations (Fig. 4). Individuals V-4 and V-5 had prenatal diagnosis in another laboratory. It is reported that these 2 patients with del(5p) were eliminated by abortion.

Haut

Discussion

The pecularity of this case is related to the extremely small chance of the mating of 2 individuals with different translocations and the occurrence of another, different translocation in the same family.

Table I summarizes the effect of dup(5p) and del(10p) on the phenotype of the propositus. No epilepsy was found in the 2 other syndromes.

Abnormal karyotypes disclosed at birth are nearly always the least unfavorable that can result from the parental translocation with the minimum loss or gain of chromosomal material [Jalbert et al., 1980). Figure 4 shows the (5;10) translocation leading to alternate or adjacent-1 segregation carriers. The adjacent-1 leads to cri du chat syndrome, caused by der5t(5;10), or to a der10t(5;10) syndrome. In our pedigree, 6 patients (IV-27, IV-35, IV-37, V-3, V-4, V-5) are der5t(5;10) carriers, and only one, the propositus, is a der10t(5;10) carrier. This can be due to translocation involving regions of the genome so important that their imbalance is highly lethal. Studies of the liveborn offspring of balanced translocation carriers have shown that predictions can be made for the mode of segregation leading to chromosomal imbalance [Jalbert et al., 1980]. The reciprocal translocations found in the family reported here were expected to segregate in different modes according to the chromosomes and breakpoints involved (Table II). Alternate segregation results in normal or balanced gametes, whereas imbalances are produced by the adjacent-I, the adjacent-2, and the 3:1 type of disjunction. The adjacent-2 and the 3:1 lead to lethal combinations, which are expected to drastically reduce the fertility of double translocation carriers. In the patient's mother, the adjacent-1 type of segregation of the (3;4) translocation also leads to lethal combinations. It is remarkable that no history of stillbirth or spontaneous abortion has been observed in the propositus mother. Only 8 possibilities of segregation lead to a viable fetus. As shown in Table II, the theoretical probability of the couple having a phenotypically normal child would be 1:2, and a genotypically normal child would be 1:8.

Table I. - A Comparison of Clinical Manifestations Found in dup(5p), del(10p), and our Propositus
Clinical findingsdup(5p)del(10p)Propositus
Life spanNf20 Months
Mental retardation+++
Growth retardation++-
Head circumferenceNNN
Large face+-+
High and flat forehead+++
Flat nasal bridge+++
Microphthalmia-++
Horizontal palpebral fissures++
Epicanthus-++
Ptosis-+-
Hypertelorism-++
Microretrognathia-++
Cleft lip-+-
Highly arched palate-++
Large ears--+
Low-set ears+++
Transverse palmarcrease---
Internal malformationsMultipleMultiple-
Epilepsy--+
Table II - Punnet square showing gamete possibilities in mating of a (3;4) balanced translocation carrier and a (5;10) balanced translocation carrier, respectively.
Chromosomes 3 and 4 Disjunction
AlternateAdjacent 1Adjacent 2
3,4 der3,der4 3,der4 4,der3 3,der3,-4 4,der4,-3
Chromosomes 5 and 10 DisjunctionAlternate 5,10Normal der3,der4 der4 der3 3,der3,-4 4,der4,-3
der5, der10der5;der10der3,der4 der5,der10der4 der5,der10der3 der5,der103,der3,-4 der5,der104,der4,-3 der5,der10
Adjacent 110,der5der5der3,der4 der5der4 der5der3 der53,der3,-4 der5 4,der4,-3 der5
5,der10der10der3,der4 der10der4 der10der3 der103,der3,-4 der104,der4,-3 der10
Adjacent 210,der10,-510,der10,-5der3,der4 10,der 1O,-5der4 10,der10,-5der3 10,der10,-53,der3,-4 10,der 1O,-54,der4,-3 10,der 1O,-5
5,der5,-105,der5,-10der3,der4 5,der5,-10der4 5,der5,-10der3 5,der5,-103,der3,-4 5,der5,-104,der4,-3 5,der5,-10

Haut