The Principles of Clinical Cytogenetics - Extra Materials - Springer

Genomic Imprinting and Uniparental Disomy 525
upd(2)pat
One case of paternal isodisomy for the entire chromosome 2 was recently reported. A 34-year-old
woman diagnosed with retinitis pigmentosa was found to have a homozygous MERTK mutation (157).
She was otherwise phenotypically normal. The patient’s father was heterozygous for the mutation
and the mother did not carry the mutation. Another case with isodisomy for paternal 2p as described
in the subsection on upd(2)mat was phenotypically normal. Paternal UPD 2 therefore does not appear
to have an imprinting effect.
upd(4)mat
A single case of maternal UPD for chromosome 4 as a result of isochromosome formation of the
short arm and long arm of chromosome 4 [i(4)(p10),i(4)(q10); see Chapters 3 and 9] was reported in
an abstract (167). Cytogenetic studies were performed because of multiple early miscarriages. The
patient was otherwise phenotypically normal. Another case with confined placental mosaicism for
trisomy 4 in a fetus with IUGR and oligohydramnios followed by intrauterine fetal death at 30 weeks
of gestation was determined to have maternal UPD 4 (168). No external malformations were detected
in this stillborn. There is no clear evidence to date that maternal UPD for chromosome 4 confers an
imprinting effect.
upd(5)pat
Paternal UPD for chromosome 5 was reported in a child with autosomal recessive spinal muscular
atrophy (169). The child had no other developmental abnormalities. Spinal muscular atrophy in this
case can be explained by the paternal transmission of two copies of the defective gene. Paternal UPD
5 is unlikely to have an imprinting effect.
upd(6)mat
Maternal uniparental isodisomy for chromosome 6 was first identified in a renal transplant patient in
the process of human leukocyte antigen (HLA) typing (170). Another patient with congenital adrenal
hyperplasia resulting from unmasking of the maternally inherited mutation in the 21-hydroxylase gene
had IUGR but good catch-up growth (171). There is no clear evidence for an imprinting effect.
upd(6)pat
More than ten cases of paternal uniparental isodisomy for chromosome 6 have been reported
(reviewed in ref. 172). All cases involve isodisomy, including two with segmental disomy (173,174).
This suggests that paternal UPD for chromosome 6 usually results from postzygotic error. Many
patients had transient neonatal diabetes mellitus (TNDM) associated with very low birth weight.
Recently, an imprinted cell cycle control gene ZAC/PLAGL1 at 6q24 with differential methylation of
parental alleles has been identified (175,176). This gene is expressed only from the paternal allele
and is a strong candidate gene for TNDM. Increased expression of this gene by paternal UPD appears
to result in the diabetic phenotype. It was estimated that paternal UPD 6 accounts for approximately
one-fifth of cases of TNDM (176). Paternal UPD 6 clearly has an imprinting effect.
upd(7)mat
More than 20 patients with maternal UPD for chromosome 7 have been reported in the literature
(25,177–179). This was the first documented UPD in humans, identified in two individuals with
cystic fibrosis and short stature (149,180). Approximately 7–10% of patients with Silver–Russell
syndrome (SRS) are noted to have maternal UPD 7 (178,179,181,182). SRS is a heterogeneous
disorder. The clinical phenotype includes intrauterine and persistent postnatal growth retardation,
body asymmetry, triangular face, prominent forehead, decreased subcutaneous tissue, delayed bone
age, and usually normal intelligence. Two regions on chromosome 7 have recently been shown to