Deficiency of the Cyclin‐Dependent Kinase Inhibitor, CDKN 1 B , Results in Overgrowth and Neurodevelopmental Delay

Germline mutations in the cyclin‐dependent kinase inhibitor, CDKN 1 B , have been described in patients with multiple endocrine neoplasia ( MEN ), a cancer predisposition syndrome with adult onset neoplasia and no additional phenotypes. Here, we describe the first human case of CDKN 1 B deficiency, which recapitulates features of the murine CDKN 1 B knockout mouse model, including gigantism and neurodevelopmental defects. Decreased m RNA and protein expression of CDKN 1 B were confirmed in the proband's peripheral blood, which is not seen in MEN syndrome patients. We ascribed the decreased protein level to a maternally derived deletion on chromosome 12p13 encompassing the CDKN 1 B locus (which reduced m RNA expression) and a de novo allelic variant (c.‐73 G > A ) in the CDKN 1 B promoter (which reduced protein translation). We propose a recessive model where decreased dosage of CDKN 1 B during development in humans results in a neuronal phenotype akin to that described in mice, placing CDKN 1 B as a candidate gene involved in developmental delay.