Segmental and full paternal isodisomy for chromosome 14 in three patients: Narrowing the critical region and implication for the clinical features

Abstract

We report on segmental and full paternal isodisomy for chromosome 14 in three previously unreported Japanese patients. Patient 1 was a 5(6/12)-year-old girl, Patient 2 was a male neonate, and Patient 3 was a -year-old girl. Physical examination at birth showed various somatic features characteristic of paternal uniparental disomy for chromosome 14 (upd(14)pat) such as hairy forehead, protruding philtrum, micrognathia, small thorax, and abdominal wall defects in Patients 1-3, and the constellation of somatic features was persistently observed in Patients 1 and 3. Radiological studies at birth delineated unique bell-shaped thorax with coat-hanger appearance of the ribs in Patients 1-3, but the thoracic deformity ameliorated in Patients 1 and 3 by mid childhood. Chromosome analysis showed a 46,XX karyotype in Patients 1 and 3 and was not performed in Patient 2. Microsatellite analysis indicated full paternal isodisomy for chromosome 14 in Patients 1 and 2 and segmental paternal isodisomy for chromosome 14 distal to D14S981 at 14q23.3 in Patient 3. Methylation specific PCR assay for the differentially methylated region (DMR) of GTL2 at 14q32 yielded positive products with methylated allele specific primers and no products with unmethylated allele specific primers in Patients 1-3. Since clinical phenotype was similar between Patient 3 with segmental upd(14)pat and Patients 1 and 2 with full upd(14)pat, the results are keeping with the 14q32 localized imprinted genes as the critical components of the phenotype observed in upd(14)pat and help narrow the search for additional genes to the approximately 40 Mb region distal to D14S981. Furthermore, it is likely that the characteristic thoracic deformity ameliorates with age.

Nonallelic Transcriptional Roles of CTCF and Cohesins at Imprinted Loci

“…Gtl2 encodes a long ncRNA with multiple spliced forms of unknown function (45,51). Gtl2 resides in the Dlk1-Dio3 imprinting cluster, which was initially identified in a uniparental disomy (UPD) of distal mouse chromosome (Chr) 12 deficiencies (56) and UPDs of the orthologous human Chr 14q32 (23). The locus contains three paternally expressed protein-coding genes (Dlk1, Rtl1, and Dio3) and a number of maternally expressed ncRNAs (Fig.…”

Novel deletions affecting the MEG3-DMR provide further evidence for a hierarchical regulation of imprinting in 14q32

“…[5][6][7][8] Genetic and epigenetic alterations affecting the imprinted gene cluster in 14q32 result in two different phenotypes currently known as maternal or paternal uniparental disomy 14 phenotypes (upd (14)mat, upd (14)pat). The upd (14)pat syndrome is characterized by polyhydramnios, a small bell-shaped thorax, facial dysmorphisms, abdominal wall defects, distal arthrogryposis and mental retardation, 9,10 whereas the upd(14)mat syndrome is characterized by pre and postnatal growth retardation, neonatal hypotonia, feeding problems and precocious puberty. [11][12][13] In both syndromes, three types of molecular alterations have been reported: uniparental disomy, deletions and epimutations.…”

Activation of paternally expressed genes and perinatal death caused by deletion of theGtl2gene

“…However, mUPD14 patients manifest short stature, small hands, scoliosis, mild developmental delay and early puberty (Kotzot, 2004). By contrast, pUPD14 patients display characteristic facial anomalies and skeletal defects (Cotter et al, 1997;Kagami et al, 2005). Recently, Stadtfeld et al (Stadtfeld et al, 2010) reported that mouse induced pluripotent stem cells (iPSCs) with repressed expression of MEGs, including Gtl2, Rian, Mirg and numerous mirRNAs, contributed poorly to chimeras and failed to generate all-iPSC mice, whereas iPSCs with normal MEG expressions contributed to high-grade chimeras and produced viable all-iPSC mice.…”