Nuclear Factor I X (“NFIX”) is a protein coding gene located in humans on the 19th chromosome at location 19p13.13. Multiple studies have shown that Marshall-Smith Syndrome is caused by a specific mutation in the NFIX gene. This mutation is heterozygous, meaning there are two different versions of a genomic marker, however, the genetic change to NFIX that causes MSS is spontaneous. In genetics, this term is called de novo, and it means that it was not inherited from either parent. All known people with MSS are the first in their families to have the syndrome.
The mutations that cause MSS have most frequently been reported in exons 6-10 of the NFIX gene. Studies in NFIX-deficient mice have shown problems with low weight gain, bone mineralization, spinal malformations, and premature death. These studies lead researchers to investigate whether the NFIX gene plays a role in the development of Marshall-Smith Syndrome. In 2010, Malan, et al, reported that 9 patients with clinically diagnosed MSS were found to have de novo mutations on the NFIX gene. Since this initial discovery, additional research has confirmed the role of NFIX mutations in the pathogenesis of MSS.
Routine prenatal genetic screening does not evaluate the NFIX gene, therefore current diagnosis usually happens in the neonatal period after clinical presentation suggests a syndromic disorder.
If within a family a child is born with MSS, and the diagnosis has been confirmed by genetic studies, the chances for another child of the same parents to have MSS are incredibly small (though not zero). Similarly, the chances that a healthy sibling of someone with MSS will produce a child with MSS are the same as everyone else in the population. In other words, every new pregnancy has the same chance of producing a child with Marshall-Smith Syndrome. There is no record of a person with MSS having children of their own.
Genetic counseling is recommended to assist with understanding these concepts.
The following disorders have clinical similarities to Marshall-Smith Syndrome: