Segmental Maternal UPD6 with Prenatal Growth Restriction

Abstract

We report a child with segmental maternal uniparental isodisomy of chromosome 6, involving most of the long arm distal to 6q16, detected by SNP microarray. Clinical features include prenatal growth restriction, global developmental delay, and severe gastro-esophageal reflux disease. Maternal uniparental disomy (UPD) of chromosome 6 has previously been reported to cause intrauterine growth restriction. Paternal UPD of this chromosome is well known to cause transient neonatal diabetes mellitus. We discuss reported cases of maternal UPD of chromosome 6 and consider whether our patient’s features may be due to disordered imprinting or unmasking of an autosomal recessive condition.

The maternal uniparental disomy of chromosome 6 (upd(6)mat) “phenotype”: result of placental trisomy 6 mosaicism?

“…Among all 17 upd(6)mat patients, five were homozygous for recessive mutations, and exhibited the respective phenotype (e.g., 3M syndrome, AGS; Table 1). In 2013, Poke and colleagues (Poke et al 2013) suggested that homozygosity of an autosomal recessive mutation in 6q16.1qter might cause some clinical features of the condition, or at least for IUGR. However, the comparison of the available SNP data in upd(6)mat patients (n = 6) reveals that there is no overlap of isodisomic regions.…”

Maternal uniparental disomy for chromosome 6 in a patient with IUGR, ambiguous genitalia, and persistent mullerian structures

“…The one case of isodisomy upd(6)mat which did not have IUGR had segmental isodisomy UPD with affected regions on the p and q arms [Gumus et al, ]. Poke et al [] noted a common region at 6q16.1qter that, when subjected to paternal UPD, resulted in IUGR. This suggested an importance of heterozygosity of this region for fetal growth, or the possible presence of an important autosomal recessive gene for growth in this region [Poke et al, ].…”

“…Poke et al [] noted a common region at 6q16.1qter that, when subjected to paternal UPD, resulted in IUGR. This suggested an importance of heterozygosity of this region for fetal growth, or the possible presence of an important autosomal recessive gene for growth in this region [Poke et al, ]. Imprinted candidate genes on chromosome 6 influencing growth have been suggested, including overexpression of maternally imprinted PLAGL1 and HYMAI genes at 6q24.2 and gain of methylation of IGFR2 (6q25.3), which may function to decrease circulating growth factor levels [Salahshourifar et al, ; Poke et al, ].…”

“…This suggested an importance of heterozygosity of this region for fetal growth, or the possible presence of an important autosomal recessive gene for growth in this region [Poke et al, ]. Imprinted candidate genes on chromosome 6 influencing growth have been suggested, including overexpression of maternally imprinted PLAGL1 and HYMAI genes at 6q24.2 and gain of methylation of IGFR2 (6q25.3), which may function to decrease circulating growth factor levels [Salahshourifar et al, ; Poke et al, ]. However, the region 6q24.2 was also found isodisomic in a patient with UPD of chromosome 6 and normal growth [Salahshourifar et al, ; Poke et al, ].…”

“…Maternal UPD of chromosome 6 (upd(6)mat) is a rare event and has only been previously reported thirteen times (Table ) [van den Berg‐Loonen et al, ; Spiro et al, ; Cockwell et al, ; Parker et al, ; Haag et al, ; Gumus et al, ; Salahshourifar et al, ; Cajaiba et al, ; Sasaki et al, ; Begemann et al, ; Poke et al, ; Roosing et al, ; Carvalho et al, ; Takimoto et al, ] with the main associated phenotype being IUGR, which has been seen in 8/10 cases with reported fetal/birth weights, and 8/9 cases having maternal isodisomy. The only recorded fetal weight that did not show IUGR, had heterodisomy 6, raising the possibility that the IUGR may be the result of homozygosity for chromosome 6 [Sasaki et al, ].…”