Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome

Pituitary stalk interruption syndrome (PSIS) is characterized by a thin or absent pituitary stalk usually in association with an ectopic posterior pituitary and hypoplasia/aplasia of the anterior pituitary. Associated phenotypes include varied ocular anomalies, hypoglycemia, micropenis/cryptorchidism, growth failure, or combined pituitary hormone deficiencies. Although genetic causes have been identified, they explain only around 5% of PSIS cases.

To identify genetic causes of PSIS by exome sequencing.

Exon enrichment was performed using the Agilent SureSelect Human All Exon V4. Paired-end sequencing was performed on the Illumina HiSeq2000 platform with an average sequencing coverage of ×50.

Patients with unexplained PSIS were included in the study.

In five cases of unexplained PSIS including two familial cases, we identified a novel heterozygous frameshift and nonsense and missense mutations in the ROBO1 gene (p.Ala977Glnfs*40, two affected sibs; p.Tyr1114Ter, sporadic case, and p.Cys240Ser, affected child and paternal aunt) that controls embryonic axon guidance, and branching in the nervous system. Interestingly, four of the five cases of PSIS also presented with ocular anomalies, including hypermetropia with strabismus as well as ptosis.

These data suggest that mutations in ROBO1 contribute to PSIS and associated ocular anomalies.