A homozygous pathogenic variant in SHROOM3 associated with anencephaly and cleft lip and palate

Neural tube defects (NTD) are among the most common congenital anomalies, affecting about 1:1000 births. In most cases, the etiology of NTD is multifactorial and the genetic variants associated with them remain largely unknown. There is extensive evidence from animal models over the past two decades implicating SHROOM3 in neural tube formation; however, its exact role in human disease has remained elusive. In this report, we present the first case of a human fetus with a homozygous loss of function variant in SHROOM3. The fetus presents with anencephaly and cleft lip and palate, similar to previously described Shroom3 mouse mutants and is suggestive of a novel monogenic cause of NTD. Our case provides clarification on the contribution of SHROOM3 to human development after decades of model organism research.