Germline CDKN1B loss-of-function variants cause pediatric Cushing's disease with or without an MEN4 phenotype.

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Germline loss-of-function CDKN1B gene variants cause the autosomal dominant syndrome of multiple endocrine neoplasia type 4 (MEN4). Even though pituitary neuroendocrine tumors are a well-known component of the syndrome, only two cases of Cushing's disease (CD) have so far been described in this setting.To screen a large cohort of CD patients for CDKN1B gene defects and to determine their functional effects.We screened 211 CD patients (94.3% pediatric) by germline whole-exome sequencing (WES) only (n=157), germline and tumor WES (n=27), Sanger sequencing (n=6) and/or germline copy number variant (CNV) analysis (n=194). Sixty cases were previously unpublished. Variant segregation was investigated in the patients' families and putative pathogenic variants were functionally characterized.Five variants of interest were found in one patient each: one truncating (p.Q107Rfs*12) and four non-truncating variants, including three missense changes affecting the CDKN1B protein scatter domain (p.I119T, p.E126Q, and p.D136G) and one 5'UTR deletion (c.-29_-26delAGAG). No CNVs were found. All cases presented early (10.5±1.3 years) and apparently sporadically. Aside from colon adenocarcinoma in one carrier, no additional neoplasms were detected in the probands or their families. In vitro assays demonstrated protein instability and disruption of the scatter domain of CDKN1B for all variants tested.Five patients with CD and germline CDKN1B variants of uncertain significance (n=2) or pathogenic/likely pathogenic (n=3) were identified, accounting for 2.6% of the patients screened. Our finding that germline CDKN1B loss-of-function may present as apparently sporadic, isolated pediatric CD has important implications for clinical screening and genetic counselling.


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