Dissecting the phenotype of supernumerary marker chromosome 20 in a patient with syndromic pierre robin sequence: Combinatorial effect of gene dosage and uniparental disomy

Abstract

Clinical phenotypes in individuals with a supernumerary marker chromosome (SMC) are mainly caused by gene dosage effects due to the genes located on the SMC. An additional effect may result from uniparental disomy (UPD). Consequently, the occurrence of UPD may be a confounding factor in identifying genotype-phenotype correlations in SMC syndromes. Here, we report on a patient that illustrates this problem; the phenotype of this patient was a consequence of a combined effect of gene dosage and UPD. The proband showed facial dysmorphisms, growth retardation and developmental delay. G-band karyotype of the proband's peripheral blood showed the presence of mosaic SMC. A SNP array analysis documented maternal UPD20 and 20p duplication. It is known that maternal UPD20 causes prenatal onset growth retardation and feeding difficulties. By contrast, duplication of 20p causes facial dysmorphisms, micrognathia, cleft palate, developmental delay and vertebral anomalies. Our classification of the proband's phenotype showed a mixture of these two effects. Therefore, we suggest the routine use of genome-wide SNP array towards the detailed genotype-phenotype correlations for SMC syndromes.

Genetic Mutations Associated with Pierre Robin Syndrome/Sequence: A Systematic Review

“…Also, abnormal karyotypes were seen in 34 cases with the reported genetic mutations [Aboura et al, 2002;Ounap et al, 2005;Velagaleti et al, 2005;Gerth-Kahlert et al, 2011;Davidson et al, 2012;Fukami et al, 2012;Izumi et al, 2012aIzumi et al, , 2015Basart et al, 2015;Capkova et al, 2017;Schoner et al, 2017]. Although all the 39 studies had assessed the genetic mutations associated with PRS, a few critical limitations were observed: All the studies were heterogeneous, and only 5 cohort studies that met the inclusion criteria were available for data analysis.…”

“…Although genetic mutations were reported in most of the studies, only 21 studies had assessed genetic mutations in the proband's family members to demonstrate familial inheritance [Melkoniemi et al, 2003;Ounap et al, 2005;Johnston et al, 2010;Gerth-Kahlert et al, 2011;Gripp et al, 2011;Izumi et al, 2012aIzumi et al, , 2015Amarillo et al, 2013;Ehmke et al, 2014;Suemori et al, 2014;Bacrot et al, 2015;Castori et al, 2016;Kohmoto et al, 2016;Xu et al, 2016;Capkova et al, 2017;Powis et al, 2017;Schoner et al, 2017;Sleiman et al, 2017;Yang et al, 2017;Højland et al, 2018;Knapp et al, 2019]. Yang et al [2017] reported genetic mutations in 3 members from a family with manifestations of nsPRS, while the family members without any clinical signs of nsPRS did not exhibit genetic mutations.…”

“…Castori et al [2016] reported a 3-generation familial inheritance of acampomelic/campomelic dysplasia char-DOI: 10.1159/000513217 acterized by PRS, bell-shaped thorax with 11 pairs of ribs, hypoplastic pedicles of the thoracic vertebrae and scapulae, narrow iliac bones, ossification delay of the pubis and cervical vertebrae, clubfeet, and bent long bones (i.e., campomelia). Izumi et al [2015] reported a nondisjunction event during oogenesis to have caused SMC syndrome due to gene dosage effects on the genes located in the supernumerary marker chromosome. The recessive inheritance model was reported by Slieman et al [2017] in Braddock-Carey syndrome which is characterized by microcephaly, congenital thrombocytopenia the Pierre-Robin sequence (PRS), and agenesis of the corpus callosum.…”

“…Figure 1 summarizes the selection strategy employed in the qualitative analysis. Table 1 summarizes the data extracted from the studies included in the systematic review [Aboura et al, 2002;Ferreira de Lima et al, 2003;Melkoniemi et al, 2003;Ounap et al, 2005;Velagaleti et al, 2005;Jakobsen et al, 2007;Manzke et al, 2008;Johnston et al, 2010;Tanpaiboon et al, 2010;Gerth-Kahlert et al, 2011;Gripp et al, 2011;Nelson et al, 2011;Said et al, 2011;Sahoo et al, 2011;Davidson et al, 2012;Fukami et al, 2012;Izumi et al, 2012aIzumi et al, , 2015Amarillo et al, 2013;Zechi-Ceide et al, 2013;Ehmke et al, 2014;Suemori et al, 2014;Takenouchi et al, 2014;Utami et al, 2014;Bacrot et al, 2015;Basart et al, 2015;Smyk et al, 2015;Braddock et al, 2016;Castori et al, 2016;Kohmoto et al, 2016;Xu et al, 2016;Capkova et al, 2017;Powis et al, 2017;Schoner et al, 2017;Sleiman et al, 2017;Yang et al, 2017;…”

“…Of the 39 included articles, 11 were from the United States of America [Velagaleti et al, 2005;Gripp et al, 2011;Nelson et al, 2011;Sahoo et al, 2011;Davidson et al, 2012;Izumi et al, 2012a;Amarillo et al, 2013;Smyk et al, 2015;Braddock et al, 2016;Powis et al, 2017;Sleiman et al, 2017], 5 from Japan [Fukami et al, 2012;Suemori et al, 2014;Takenouchi et al, 2014;Izumi et al, 2015;Kohmoto et al, 2016], 5 from Germany [Ounap et al, 2005;Manzke et al, 2008;Gerth-Kahlert et al, 2011;Ehmke et al, 2014;Schoner et al, 2017], 2 from France [Aboura et al, 2002;Bacrot et al, 2015], 2 from Brazil [Ferreira de Lima et al, 2003;Zechi-Ceide et al, 2013], 2 from Italy [Castori et al, 2016;Roberti et al, 2018], 2 from Denmark [Jakobsen et al, 2007;Højland et al, 2018], 1 each from Belgium [Said et al, 2011], Singapore [Utami et al, 2014], Netherlands [Basart et al, 2015], China [Yang et al, 2017], Finland [Melkoniemi et al, 2003], Thailand [Tanpaiboon et al, 2010], Czech Republic [Capkova et al, 2017], New Zealand [Knapp et al, 2019], Canada…”