JG Hall, F Solehdin

In a normal human genome, one chromosome of each pair is maternally and the other paternally inherited. Uniparental disomy (UPD) describes a specific genetic constitution in which both members of a chromosome pair are inherited from a single parent (i.e. unimaternal or unipaternal disomy). UPD is surprisingly common. The primary mechanism producing uniparental disomy appears to be trisomy rescue after meiotic non disjunction (i.e. failure of chromosomes to separate properly during reduction to 23 chromosomes in the formation of the egg or sperm) associated with advanced maternal age with the conversion of some cells of the trisomy embryo to the normal disomic state.^1-2

As many as 20% of pregnancies begin as trisomy. Most trisomic conceptions are lethal and the embryo is aborted except for trisomy 13, 18 and 21 which may go to term. The only way most trisomic fetus can survive is by elimination of one of the chromosomes, producing a viable disomic cell line (i.e. 2 copies of the chromosome). Since there are two chromosomes from one parent in the trisomy, when loss of one chromosome occurs, one third of the time, the loss will result in uniparental disomy i.e. both remaining chromosome come from that one parent. Chorionic villus sampling for prenatal diagnosis at 9-11 weeks show that 2-3% of the fetuses have placental mosaicism for trisomy and thus as many as 1% of all ongoing pregnancies may carry uniparental disomy for a particular chromosome which occurs as a result of recovering trisomies.³ If both copies of the two different chromosomes are inherited from one parent it is termed heterodisomy. If two identical copies of the same chromosome are inherited from one parent this is termed isodisomy.

Three types of effects are seen with uniparental disomy

1. Imprinting
2. Autosomal recessive disorders
3. Residual aneuploidy

Review of Reported Cases of Uniparental Disomy

Uniparental disomy is now known to occur in a number of known disorders and has been documented for the autosomes 2, 4, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 21, & 22, and the sex chromosomes.

Chromosome 2

Maternal uniparental disomy of chromosome 2 in a baby with trisomy 2 mosaicism in amniotic fluid culture has been documented. The baby is reported to have had growth failure, hypothyroidism and acute respiratory distress in the neonatal period. The associated findings could be due to imprinted genes on this chromosome.⁴

Chromosome 4

Maternal UPD of chromosome 4 has been demonstrated with no phenotypic effects in a normal female who was evaluated for multiple early miscarriages suggesting that no phenotypic abnormalities occur with two maternal chromosomes 4.⁵

Chromosome 5

Paternal isodisomy for chromosome 5 has been reported in a two year old boy with type III spinal muscular atrophy. Spinal muscular atrophy is an autosomal recessive degenerative disorder of the alpha motor neurons.⁶ Only the father carried the abnormal gene.

Chromosome 6

Paternal UPD of chromosome 6 is associated with transient neonatal diabetes mellitus and growth retardation. A double dose of paternal chromosome 6 is responsible for this condition. These babies lack insulin in the neonatal period but this is spontaneously produced by six months. It usually improves during the first year but definitely by three years of age. Cases of transient neonatal diabetes mellitus with paternal UPD of chromosome 6 have been described with complement 4 deficiency and metabolic disorder.^7-10

Chromosome 7

Maternal UPD of chromosome 7 is associated with intrauterine growth retardation as well as post-natal growth retardation. This has been observed in patients with maternal UPD for chromosome 7 with or without cystic fibrosis,^11-12 Russell-Silver syndrome¹³ and osteogenesis imperfecta.¹⁴ Paternal UPD for chromosome 7 is compatible with normal growth and development and appears to cause no phenotypic effects. Maternal UPD of chromosome 7 has been reported with sporadic cases of Russell-Silver syndrome associated with both prenatal and post natal growth retardation. Russell-Silver syndrome is characterized by prenatal and post natal growth retardation, disproportionately large head with a triangular face, delayed closure of the anterior fontanelle, down turned corners of the mouth, hemihypotrophy of face, areas of hypo- or hyperpigmentation of the skin, cryptorchidism / hypospadias. Screening for UPD 7 in patients with features of Russel Silver patients have revealed that about 10% patients with Russel Silver have maternal UPD of chromosome 7.

Chromosome 8

Complete paternal isodisomy for chromosome 8 has been revealed by lipoprotein lipase deficiency in a child who had inherited an abnormal gene from the heterozygous carrier father. The gene encoding lipoprotein lipase maps to human chromosome 8p22.¹⁵

Chromosome 9

A case of maternal uniparental disomy of chromosome 9 in fetal tissues of a terminated pregnancy associated with confined placental mosaicism for trisomy 9 has been reported.¹⁶

Chromosome 10

Maternal UPD of chromosome 10 has been reported associated with confined placental mosaicism in an apparently normal phenotype suggesting that there are no major imprinted genes. However, other potential effects such as mental retardation will require long-term follow-up of the case with additional study of cases.¹⁷

Chromosome 11

Paternal lip UPD, partial isodisomy of lip, and maternal translocation of lip is associated with Beckwith-Weidemann syndrome. Beckwith-Weidemann syndrome is a fetal overgrowth syndrome associated with excess insulin and is characterized by visceromegaly, macroglossia, omphalocele and hypoglycemia in the neonatal period. It is a very confusing syndrome and its etiology is still to be fully determined. Only a subset of patients (about 20% of sporadic cases with Beckwith-Weidemann syndrome) have been shown to have uniparental disomy of paternal lip chromosome.^18,19 Patients with Beckwith-Weidemann syndrome have a 50% higher risk of developing Wilms tumor. In a small proportion of cases in which Beckwith-Weidemann syndrome is associated with paternal lip UPD the two paternal copies of insulin like growth factor 2 are expressed. Insulin like growth factor 2 is a paternally expressed (expressed from the paternally derived chromosome) growth enhancer gene thus paternal lip UPD leads to the excess of expressed paternal alleles observed in the Beckwith-Weidemann syndrome.

A case of paternal uniparental disomy for chromosome 11 has also been reported with severe intrauterine growth retardation, intrauterine death, intestinal rotation and hypospadias.²⁰ This suggests that there may be several imprinted genes on this chromosome or that the effect of trisomy in a mosaic placenta can effect fetal growth.

Chromosome 13

Not all cases of UPD have abnormal growth. Uniparental maternal disomy of chromosome 13 has been documented in normal phenotypes. It has been described in a phenotypic normal male who inherited the translocation from the mother. The mother was a phenotypically normal carrier of the translocation with a history of recurrent abortion.²¹

Chromosome 14

Maternal UPD for chromosome 14 is associated with a distinct phenotype and is characterized by short stature, precocious puberty, arrested hydrocephalus, small hands and feet, scoliosis, delayed motor and/or mental development, and recurrent otitis media.²²

Maternal UPD of chromosome 14 has also been associated with autosomal rod monochromacy (complete congenital achromatopsia) suggesting the location for the gene.²³ This disorder is inherited as an autosomal recessive trait and is characterized by total absence of color discrimination.

Maternal uniparental isodisomy of human chromosome 14 associated with paternal T (13q14q) and precocious puberty has been reported suggesting imprinted genes on chromosome 14, involved in the onset of puberty.²⁴

A case of paternal UPD for chromosomal 14 has been reported in a baby born prematurely with hairy forehead, retrognathia, mild puckering of the lips finger contractures, hypotonia and laryngomalacia.²⁵

Chromosome 15

The two syndromes studied extensively for the effects of uniparental disomy and imprinting are Prader-Willi and Angelman syndromes. Both are distinct neurobehavioral disorders although both are seen with UPD 15 suggesting that there are genes and critical region with distinct functions required to prevent the two disorders. Prader-Willi syndrome is a disorder that presents with a round face, obesity, mild mental retardation and hypogonadism; associated with absence of paternal contribution of chromosome 15 and maternal UPD for chromosome 15. Whereas Angelman syndrome, on the other hand presents with a very long face, severe mental retardation and uncontrolled bouts of laughter and seizures; associated with absence of a maternal contribution of chromosome 15 and paternal UPD for chromosome 15.²⁶ Mascari, et al.²⁷ reports a high frequency of occurrence of UPD in Prader-Willi syndrome. About 30-35% of all PWS that were examined showed maternal uniparental disomy and are associated with advanced maternal age suggesting that the disomic line is derived from trisomy whereas^28,29 reported a frequency of paternal disomy in only 3-4% of Angelman syndrome patients.

Trisomy 15 mosaicism and UPD a very rare event has been reported recently in an infant who died at the age of six weeks. The infant was growth retarded with distinct craniofacies, congenital heart disease, severe hypotonia and minor skeletal anomalies. Trisomy was detected in the skin fibroblasts but not in the blood.³⁰

Maternal UPD for chromosome 15 has recently been described in a child with Bloom syndrome suggesting gene location on this chromosome.³¹

Chromosome 16

A case of maternal UPD of chromosome 16 has been shown to be linked to intrauterine growth retardation and imperforate anus. The intrauterine growth retardation correlating with high levels of trisomy 16 in the placentas. Maternal UPD of chromosome 16 has been reported in normal phenotypes as well as with major birth defects associated with anal atresia and hypospadias and with recessive inheritance of familial Mediterranean fever (FMF) from their mothers.^32,33 Gene for familial Mediterranean fever (FMF) has been mapped to 16p13.3-p13.1.34³⁴

Chromosome 21

A single case of UPD 21 with a normal phenotype has been reported.³⁵

Chromosome 22

Maternal uniparental disomy 22 has been reported in a 25 year normal healthy male who was karyotyped because five of his wife's pregnancies terminated in spontaneous abortions.³⁶

Robertsonian translocation and the risk for UPD

The frequency of Robertsonian translocations is about 1 in 10,000 live births. It may be an important cause of UPD for 13/15, 13/14, 14/14, and 22/22 translocations. The risk of UPD must be considered in cases when there is infertility, repeated abortions and aneuploid offsprings. The mother may be a carrier of a balanced translocation and may pass on the translocation to the offspring. In such cases dysmorphic features and / or mental retardation will provide clinical clues for uniparental disomy in apparently balanced offspring carriers.

Sex chromosomes

A case of father to son transmission has been reported in hemophilia;³⁷ which is an X-linked recessive disorder transmitted to sons by the mother who is a carrier of the defective gene. In this particular case the mother was not a carrier and the son had received both X and Y chromosome from the father {in normal circumstances the father contributes the Y chromosome to the son and the X chromosome is inherited from the mother}. Thus the maternal X chromosome must have been lost.

A case of Turner syndrome with 45X/46, XX in which both the X chromosomes were inherited from the father has been described by Schinzel et al. The patient had short stature but few stigmata of Turner syndrome.³⁸

Effects of Uniparental Disomy

1. Autosomal recessive disorders

Uniparental isodisomy must be kept in mind, particularly in sporadic autosomal recessive disorders when only one of the parent is found to be a carrier of the recessive gene. If the offspring inherits 2 copies of exactly the same chromosome (isodisomy) it may receive a double dose of an abnormal gene (2 copies); the child is now homozygous for the mutant gene and will express the recessive disorder although both copies of the defective gene have been inherited from one carrier parent only. This situation is seen rarely in cystic fibrosis (CF). In such cases the affected children have received both of their copies of chromosome 7 from the mother and the father was not a carrier of the recessive gene. The autosomal diseases associated with uniparental disomy which have been reported include spinal muscular atrophy associated with paternal isodisomy of chromosome 5, complement deficiency, cystic fibrosis, osteogenesis imperfecta, congenital chloride diarrhea, cartilage hair hypoplasia, beta-thalassemia, retinoblastoma, rod monochromacy, Bloom syndrome, alpha thalassemia, familial Mediterranean fever, and hemophilia (refer to Table). Only one parent produced the autosomal recessive disorder!

2. Genomic imprinting effects

Imprinting is said to have occurred when the genes in a critical chromosomal region are expressed only on the chromosome inherited from one parent. The other parent's chromosome with the genes is present but is not expressed. Imprinting effects have been observed in humans for several chromosomes including chromosome 7. The lack of paternal chromosome 7 is associated with intrauterine growth deficiency as well as post-natal growth retardation. In other words there is something on the paternal chromosomes necessary for normal growth. This has been observed with some cystic fibrosis patients with maternal UPD for chromosome 7^11,39 as well as without cystic fibrosis. Intrauterine growth retardation is seen in Russell Silver syndrome and about 10% of Russell Silver syndrome may have maternal UPD of chromosome 7.

3. Residual aneuploidy

Significance for chorionic villas sampling

Chorionic villus sampling enables the identification of those fetuses having placental mosaicism. It has now been found that the incidence of trisomy mosaicism in non-lethal trisomies is higher than previously anticipated. This gives the opportunity to look for trisomic fetuses who are then rescued by conversion to disomic lines by the elimination of the extra chromosome but making the fetus at risk for having uniparental disomy. Chorionic villus sampling is now done routinely for women of advanced maternal age who are at risk for non-disjunction and therefore may give birth to trisomic infants (usually those with Down syndrome). It is difficult to estimate the frequency of recovering trisomies producing a disomic line in mothers who are less than 35 years because they are not routinely screened through this procedure.

Clinical Implications

1. Suspect uniparental disomy in an unusual child with an autosomal recessive disorder or two autosomal diseases with different phenotypes.

2. Consider the possibility of UPD in cases when there is infertility, repeated abortions and aneuploid offsprings. The mother may be a carrier of a balanced translocation and may pass on the translocation to the offspring. Dysmorphic features and/or mental retardation will provide clinical clues for uniparental disomy in apparently balanced offspring of translocation carriers.

3. UPD can be diagnosed prenatally by chorionic villus sampling - If placental mosaicism is found then UPD should be suspected and tested for. About one third of the time surviving trisomy will result in UPD. UPD occurs if the trisomic fetus looses one of the trisomic chromosome producing a viable disomic line in order for the fetus to survive.

4. Diagnosis of uniparental disomy must be considered in children with intrauterine growth retardation because recently about 10% of Russell-Silver syndrome patients have been found to have maternal uniparental disomy of chromosome 7 (i.e. two copies of mothers chromosome and no copy from the father - maternal duplication/paternal deficiency). In view of this finding all individuals with Russell-Silver syndrome should have molecular genetic evaluations. This may explain the 10% of Russell-Silver syndromes.

5. Carriers of Robertsonian translocation are at increased risk of uniparental disomy. Although its frequency is low this should be considered.

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