Paternal uniparental disomy chromosome 14-like syndrome due a maternal de novo 160 kb deletion at the 14q32.2 region not encompassing the IG- and the MEG3-DMRs: Patient report and genotype-phenotype correlation.
The human chromosome 14q32 carries a cluster of imprinted genes which include the paternally expressed genes (PEGs) DLK1 and RTL1, as well as the maternally expressed genes (MEGs) MEG3, RTL1as, and MEG8. PEGs and MEGs expression at the 14q32.2-imprinted region are regulated by two differentially methylated regions (DMRs): the IG-DMR and the MEG3-DMR, which are respectively methylated on the paternal and unmethylated on the maternal chromosome 14 in most cells. Genetic and epigenetic abnormalities affecting these imprinted gene clusters result in two different phenotypes currently known as maternal upd(14) syndrome and paternal upd(14) syndrome. However, only few patients carrying a maternal deletion at the 14q32.2-imprinted critical region have been reported so far. Here we report on the first patient with a maternal de novo deletion of 160 kb at the 14q32.2 chromosome that does not involves the IG-DMR or the MEG3-DMR but elicits a full upd(14)pat syndrome's phenotype encompassing the three mentioned MEGs. By the analysis of this unique genotype-phenotype correlation, we further widen the spectrum of the congenital anomalies associated to this rare disorder and we propose that the paternally expressed imprinted RTL1 gene, as well as its maternally expressed RTL1as antisense transcript, may play a prominent causative role.
Department of Sciences for Health Promotion and Mother and Child Care, Università di Palermo, Palermo, Italy.
Giovanni
G
Corsello
Department of Sciences for Health Promotion and Mother and Child Care, Università di Palermo, Palermo, Italy.
Emanuela
E
Salzano
Department of Sciences for Health Promotion and Mother and Child Care, Università di Palermo, Palermo, Italy.
Davide
D
Vecchio
Department of Sciences for Health Promotion and Mother and Child Care, Università di Palermo, Palermo, Italy.
Vincenzo
V
Antona
Laboratory of Human Genetics, Galliera Hospital, Genoa, Italy.
Marina
M
Grasso
Laboratory of Human Genetics, Galliera Hospital, Genoa, Italy.
Michela
M
Malacarne
Medical Genetics Service, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
Massimo
M
Carella
Medical Genetics Service, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
Pietro
P
Palumbo
Department of Sciences for Health Promotion and Mother and Child Care, Università di Palermo, Palermo, Italy.
Ettore
E
Piro
Department of Sciences for Health Promotion and Mother and Child Care, Università di Palermo, Palermo, Italy.
Mario
M
Giuffrè
D002135:Calcium-Binding Proteins; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D010641:Phenotype; D011257:Pregnancy Proteins / Q000235:genetics; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics; D017384:Sequence Deletion; D013577:Syndrome; D024182:Uniparental Disomy / Q000235:genetics* / Q000473:pathology; D000096803:Imprinting Disorders
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C498907:MEG3 non-coding RNA, human; D008565:Membrane Proteins; D011257:Pregnancy Proteins; D062085:RNA, Long Noncoding; C579465:RTL1 protein, human
14q32.2 imprinted region; 14q32.2 maternal deletion; IG-DMR; MEG3 gene; MEG3-DMR; RTL1as gene; paternal uniparental disomy chromosome 14 [upd(14)pat]; skeletal dysplasia; “coat-hanger“ rib sign