Marshall-Smith and Malan syndrome are caused by a change (mutation) in the NFIX gene. The most common variant types leading to Marshall Smith syndrome are frameshift and splice site variants and dominant negative action (abnormal product interferes with action of normal product of gene) is the underlying pathomechanism. Most common variant leading to Malan syndrome are nonsense, missense, frameshift and whole/partial gene deletions and haploinsufficiency (less than normal product of gene) is the underlying pathomechanism. Most individuals are the first individuals in the families to have this syndrome and hence they are called “de novo” cases.
Hence risk of recurrence in the siblings is not increased. However, occasional cases of recurrence due to mosaicism in the parent is reported.
NFIX