Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy

Abstract

BackgroundInterstitial microdeletion 14q22q23 is a rare chromosomal syndrome associated with variable defects: microphthalmia/anophthalmia, pituitary anomalies, polydactyly/syndactyly of hands and feet, micrognathia/retrognathia. The reports of the microdeletion 14q22q23 detected in the prenatal stages are limited and the range of clinical features reveals a quite high variability.Case presentationWe report a detection of the microdeletion 14q22.1q23.1 spanning 7,7 Mb and involving the genes BMP4 and OTX2 in the foetus by multiplex ligation-dependent probe amplification (MLPA) and verified by microarray subsequently. The pregnancy was referred to the genetic counselling for abnormal facial profile observed in the first trimester ultrasound scan and micrognathia (suspicion of Pierre Robin sequence), hypoplasia nasal bone and polydactyly in the second trimester ultrasound scan. The pregnancy was terminated on request of the parents.ConclusionAn abnormal facial profile detected on prenatal scan can provide a clue to the presence of rare chromosomal abnormalities in the first trimester of pregnancy despite the normal result of the first trimester screening test. The patients should be provided with genetic counselling. Usage of quick and sensitive methods (MLPA, microarray) is preferable for discovering a causal aberration because some of the CNVs cannot be detected with conventional karyotyping in these cases. To the best of our knowledge, this is the earliest detection of this microdeletion (occurred de novo), the first case detected by MLPA and confirmed by microarray. Literature review of the genotype-phenotype correlation in similar reports leads us to the conclusion that dosage imbalance of the chromosomal segment 14q22q23 (especially haploinsuffiency of the genes BMP4 and OTX2) contributes significantly to orofacial abnormalities. Association of the region with the Pierre Robin sequence appears to be plausible.

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

“…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…”

“…The patient was the first adult to be diagnosed with TARP syndrome with a milder phenotype that leads to survival to adulthood. kobsen et al, 2007;Basart et al, 2015;Xu et al, 2016], 10 were case series [Velagaleti et al, 2005;Johnston et al, 2010;Nelson et al, 2011;Sahoo et al, 2011;Zechi-Ceide et al, 2013;Ehmke et al, 2014;Bacrot et al, 2015;Braddock et al, 2016;Castori et al, 2016;Yang et al, 2017], and 24 were case reports [Aboura et al, 2002;Ounap et al, 2005;Manzke et al, 2008;Tanpaiboon et al, 2010;Gerth-Kahlert et al, 2011;Gripp et al, 2011;Said et al, 2011;Davidson et al, 2012;Fukami et al, 2012;Izumi et al, 2012a;Amarillo et al, 2013;Suemori et al, 2014;Takenouchi et al, 2014;Utami et al, 2014;Smyk et al, 2015;Kohmoto et al, 2016;Capkova et al, 2017;Powis et al, 2017;Schoner et al, 2017;Sleiman et al, 2017;Højland et al, 2018;Roberti et al, 2018;Knapp et al, 2019].…”

“…Thorough knowledge of the genetic mutations associated with the syndrome could aid in the early confirmatory diagnosis of the disease and formulate an appropriate treatment plan. It is an interesting fact that PRS and genetic mutations associated with PRS could be detected during the prenatal period as early as the first trimester of pregnancy [Capkova et al, 2017]. This would help the parents to decide upon medical termination of pregnancy based on the severity of the syndrome.…”

Dental and Craniofacial Characteristics in Patients With 14Q22.1-Q22.2 Deletion: A Case Series

“…Depending on the size of the deletion, one or multiple genes can be affected. Haploinsufficiency of multiple contiguous genes such as the BMP4 (bone morphogenic protein 4), OTX2 (orthodenticle homeobox 2 gene), SIX6 (sine oculis homeobox, drosophilia, homoglog OF), GCH1 (GTP cyclohydrase 1 gene), or TMEM260 (transmembrane protein 260) usually results in a more severe eye phenotype with additional syndromic features (Nolen et al, 2006; Bakrania et al, 2008; Capkova et al, 2017; Lohmann et al, 2017).…”