Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients

J Clin Endocrinol Metab. 2018 Feb 1;103(2):415-428. doi: 10.1210/jc.2017-01660.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • DNA Mutational Analysis / methods*
  • Exome
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing / methods*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Multifactorial Inheritance* / genetics
  • Pituitary Diseases / congenital
  • Pituitary Diseases / genetics*
  • Pituitary Gland / abnormalities*
  • Sequence Analysis, DNA / methods
  • Syndrome
  • Young Adult