Nitash Zwaveling-Soonawala1, Marielle Alders2, Aldo Jongejan3, Lidija Kovacic4, Floor A Duijkers2, Saskia M Maas2, Eric Fliers5, A S Paul van Trotsenburg1, Raoul C Hennekam6. 1. Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. 2. Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. 3. Department of Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. 4. Novartis Ireland Ltd, Beech Hill Office Campus, Dublin, Ireland. 5. Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. 6. Department of Pediatrics, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Abstract
Context: Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. Objective: To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Methods: Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. Results: We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Conclusion: Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.
Context:Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. Objective: To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Methods: Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. Results: We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Conclusion: Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.
Authors: Bartlomiej Budny; Tomasz Zemojtel; Malgorzata Kaluzna; Pawel Gut; Marek Niedziela; Monika Obara-Moszynska; Barbara Rabska-Pietrzak; Katarzyna Karmelita-Katulska; Marek Stajgis; Urszula Ambroziak; Tomasz Bednarczuk; Elzbieta Wrotkowska; Ewelina Bukowska-Olech; Aleksander Jamsheer; Marek Ruchala; Katarzyna Ziemnicka Journal: Front Endocrinol (Lausanne) Date: 2020-06-16 Impact factor: 5.555
Authors: Sebastian Alexis Vishnopolska; Maria Florencia Mercogliano; Maria Andrea Camilletti; Amanda Helen Mortensen; Debora Braslavsky; Ana Keselman; Ignacio Bergadá; Federico Olivieri; Lucas Miranda; Roxana Marino; Pablo Ramírez; Natalia Pérez Garrido; Helen Patiño Mejia; Marta Ciaccio; Maria Isabel Di Palma; Alicia Belgorosky; Marcelo Adrian Martí; Jacob Otto Kitzman; Sally Ann Camper; Maria Ines Pérez-Millán Journal: J Clin Endocrinol Metab Date: 2021-06-16 Impact factor: 6.134