TY - JOUR
T1 - Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients
AU - Zwaveling-Soonawala, Nitash
AU - Alders, Marielle
AU - Jongejan, Aldo
AU - Kovacic, Lidija
AU - Duijkers, Floor A.
AU - Maas, Saskia M.
AU - Fliers, Eric
AU - van Trotsenburg, A. S. Paul
AU - Hennekam, Raoul C.
PY - 2018
Y1 - 2018
N2 - 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
AB - 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
U2 - https://doi.org/10.1210/jc.2017-01660
DO - https://doi.org/10.1210/jc.2017-01660
M3 - Article
C2 - 29165578
SN - 0021-972X
VL - 103
SP - 415
EP - 428
JO - Journal of clinical endocrinology and metabolism
JF - Journal of clinical endocrinology and metabolism
IS - 2
ER -