The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age

Abstract

Most instances of maternal uniparental disomy (UPD) start as trisomies and, similar to the latter, show a significant increase of mean maternal age at delivery. To investigate the incidence of UPD in offspring of older mothers, we investigated two groups of patients: 1) 50 patients with unclassified developmental defects born to mothers 35 years or older at delivery were tested for UPD for all autosomes by means of microsatellite marker analysis; 2) The incidence of UPD versus other etiologies in correlation, with maternal age below versus 35 years and above at delivery was studied in patients investigated in our laboratory for maternal UPD 15 (Prader-Willi syndrome, PWS), paternal UPD 15 (Angelman syndrome, AS), and maternal UPD 7 (Silver-Russell syndrome, SRS). In group 1, four patients of 50 showed UPD for an autosome that clarified the etiology of their developmental problems: a 27-year-old woman with growth retardation and early puberty disclosed maternal heterodisomy 14; a 15-year-old girl revealed paternal isodisomy 15; a 6-year-old boy with suspected Smith-Lemli-Opitz syndrome was shown to have maternal heterodisomy 16 with additional mosaic partial trisomy 16(pter-p13); a 16-month-old girl with intrauterine growth retardation and a dysmorphic pattern revealed maternal heterodisomy 7. In group 2 the offspring of older mothers showed a clear increase of UPD compared with the mothers below 35 years at delivery. The binomial distribution gave P-values of 1.9 x 10(-10), 2.6 x 10(-4), and 0.01 for PWS, AS, and SRS, respectively. The correlation between increase of paternal UPD 15 with advanced maternal age might be explained by maternal non-disjunction leading to hypohaploid gamete (nullisomy) for chromosome 15 with subsequent or concomitant duplication of the paternal homologue (paternal isodisomy). The three UPD 15 AS cases with mothers older than 35 years at delivery revealed isodisomy, whereas the three cases from younger mothers showed heterodisomy. This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers.

Different distribution of the genetic subtypes of the Prader–Willi syndrome in the elderly

“…This relation has been ascribed to the mechanism of nondysjunction during meiosis, forming a trisomic zygote and the subsequent loss of the paternal homologue, resulting in mUPD. 11 In recent years, assisted reproductive technologies (ART) have been studied extensively as a potential factor involved in the molecular cause of genetic abnormalities. One report suggested an elevated risk of birth defects and genetic abnormalities associated with infertility and treatment with ART.…”

Paternal uniparental disomy of chromosome 14 and unique exchange of chromosome 7 in cases of spontaneous abortion

“…To the best of our knowledge, of the UPD 14 cases in liveborns reported to date in the literature, 37 were mat (Antonarakis et al 1993;Papenhausen et al 1995;Barton et al 1996;Tomkins et al 1996;Splitt and Goodship 1997;Harrison et al 1998;Miyoshi et al 1998;Hordijk et al 1999;Martin et al 1999;Ralph et al 1999;Ginsburg et al 2000;Manzoni et al 2000;Sanlaville et al 2000;Eggermann et al 2001;Katahira et al 2002;Cox et al 2004) and 8 pat (Wang et al 1991;Papenhausen et al 1995;Walter et al 1996;Cotter et al 1997;McGowan et al 2002;Coveler et al 2002;Kurosawa et al 2002;Offiah et al 2003). As mentioned above, most cases of pat UPD 14 have characteristic and often serious clinical features, including blepharophimosis, small thorax, and joint contractures, while the main features of mat UPD 14 are low birth weight, poor postnatal growth, fleshy nasal tip, and scoliosis.…”

Uniparental disomy of chromosome 8 leading to homozygosity of a <i>CYP11B1</i> mutation in a patient with congenital adrenal hyperplasia: Implication for a rare etiology of an autosomal recessive disorder

“…Our data provide a novel example of autosomal recessive disorders resulting from UPD. Given the rise in the number of births associated with advanced maternal age that represents a possible predisposing factor of oocyte aneuploidy and UPD [6,7,11], UPD should be regarded as an important cause of congenital disorders. Indeed, carrier status of the parents should be examined before genetic counseling of families with autosomal recessive disorders including CAH, because the recurrence risk of such disorders is 25% in the majority of cases, and low or negligible when the disease is associated with UPD or de novo mutations.…”