NBPF9 Gene May Be Involved in Congenital Hypopituitarism: A Whole-Genome Study of a Boy with Pituitary Stalk Interruption Syndrome and His Family

Abstract

Pituitary stalk interruption syndrome (PSIS) is a rare congenital defect manifesting as various degrees of anterior pituitary hormone deficiency. Scattered familial cases have been found, revealing some genetic variants. However, most of the previous research studies involved an affected sibling, and the gene spectra of the patients’ entire family have rarely been reported. We conducted a study of a family consisting of a PSIS patient with his unaffected sibling and healthy parents of Han Chinese background using whole-genome sequencing. Bioinformatic analysis was carried out, and mutations related to PSIS, single-nucleotide variants (SNVs), insertion-deletion (InDELs), and structural variations (SVs) in all the four samples were filtered. After Sanger sequencing, we confirmed the variants obtained and selected three candidate genes for functional verification. The gene variations in this boy with PSIS and his lineal relatives are reported herein; de novo sequencing revealed that the NBPF9 gene may be involved in the pathogenesis of PSIS.

Successful pregnancy and delivery in a Chinese female with pituitary stalk interruption syndrome following in vitro fertilization and embryo transfer: a case report and literature review

“…Fanconi's anemia, a rare autosomal recessive hematological disease, was also observed to be accomplished by PSIS [23], suggesting that gene mutations may play a signi cant role in the pathogenesis of PSIS. In humans, multiple gene mutations or sequence variants in PROP1, PTCH1, PTCH2, LHX4, POU1F1, HESX1, OTX2, SOX3, NBPF9 and GPR161 and so on, have been postulated to be involved in PSIS [24][25][26]. Brauner et al [27] performed exome sequencing in 52 PSIS cases and found that rare and novel genetic variants were identi ed in 75% of PSIS patients, which mainly involved in midline development and/or pituitary development or function, syndromic and non-syndromic forms of hypogonadotropic hypogonadism, syndromic forms of short stature, cerebellum atrophy with optic anomalies, axonal migration, and agenesis of the corpus callosum.…”

Re-analysis of gene mutations found in pituitary stalk interruption syndrome and a new hypothesis on the etiology

“…Kaygusuz et al described a novel FOXA2: c.616C >T, p.Q206X variant in one PSIS patient, causing impaired GLUT2-luciferase activation due to a truncated protein (19). Wang et al observed a significant reduction in LHX3 expression when NBPF9 was knocked down in human embryonic stem cells (25). Su et al found that silencing the CDC27 gene inhibits both migration and secretion functions in GH3 cells.…”