NFIX – Malan Overgrowth Syndrome

Malan overgrowth syndrome (MONDO:0013885) is an autosomal dominant overgrowth disorder characterized by postnatal overgrowth, macrocephaly, intellectual disability, and distinctive facial features. Pathogenic variants in NFIX (HGNC:7788) underlie this syndrome, with most mutations occurring de novo and clustering in exon 2, leading to haploinsufficiency ([PMID:29897170]). Clinical features overlap with Sotos syndrome but are distinguished by the absence of NSD1 variants and distinctive craniofacial findings.

Genetic evidence includes 45 molecularly confirmed probands, each with heterozygous NFIX point mutations or whole-gene deletions ([PMID:29897170]). Additional cases have been reported in singleton case reports, including a novel c.290_291insA frameshift variant in exon 2 ([PMID:28584646]) and a 990 kb deletion encompassing NFIX ([PMID:31574590]). Segregation analysis revealed two brothers sharing a paternal NFIX variant due to gonadal mosaicism, underscoring recurrence risk beyond standard de novo expectations ([PMID:31369202]).

Variant spectrum comprises predominantly protein-truncating alleles triggering nonsense-mediated mRNA decay (LoF) and missense changes within the N-terminal DNA-binding domain. Reported variant types include frameshift insertions (e.g., c.290_291insA), whole‐gene deletions, intragenic duplications, and missense substitutions such as c.343C>T (p.Arg115Trp). No recurrent founder alleles have been described to date.

Functional studies support a haploinsufficiency mechanism. An intragenic NFIX duplication encompassing exons 6–7 leads to reduced transcript levels via NMD, consistent with loss-of-function ([PMID:38168088]). Murine models of exon 7 deletions recapitulate NFIX dominant-negative effects in skeletal and neural tissues, differentiating Malan from Marshall-Smith syndromes based on NMD escape ([PMID:37283649]).

No studies have refuted the NFIX–Malan link; genotype-phenotype correlation remains limited by cohort size. The consistency of de novo occurrence, segregation in mosaicism, and concordant functional data supports a strong gene-disease relationship.

Key Take-home: Heterozygous NFIX loss-of-function variants cause autosomal dominant Malan syndrome, which should be considered in patients with overgrowth, macrocephaly, and intellectual disability; accurate molecular diagnosis informs recurrence risk, including potential parental mosaicism.

References

• Human Mutation • 2018 • Further delineation of Malan syndrome PMID:29897170
• Human Genome Variation • 2017 • A novel mutation of NFIX causes Sotos-like syndrome (Malan syndrome) complicated with thoracic aortic aneurysm and dissection. PMID:28584646
• Molecular Genetics & Genomic Medicine • 2019 • Malan syndrome in a patient with 19p13.2p13.12 deletion encompassing NFIX and CACNA1A genes: Case report and review of the literature. PMID:31574590
• American Journal of Medical Genetics Part A • 2019 • Parental gonadal but not somatic mosaicism leading to de novo NFIX variants shared by two brothers with Malan syndrome. PMID:31369202
• American Journal of Medical Genetics Part A • 2024 • Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon-level Array, and RNA sequencing. PMID:38168088
• JBMR Plus • 2023 • A Mouse Model with a Frameshift Mutation in the Nuclear Factor I/X (NFIX) Gene Has Phenotypic Features of Marshall-Smith Syndrome. PMID:37283649

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