Genetic and clinical insights into MAST4-related neurodevelopmental disorders

Abstract

Objective: De novo variants in MAST4 are increasingly implicated in neurodevelopmental disorders (NDDs), but the associated phenotypic spectrum remains incompletely characterized. We report a Chinese child with global developmental delay (GDD) and a novel MAST4 variant, further delineating the genotype-phenotype correlations for this gene.

Methods: Clinical and genetic data were retrospectively analyzed for a proband diagnosed with a MAST4-related NDD at Fujian Children's Hospital. Trio-based whole-exome sequencing (WES) and subsequent Sanger sequencing were performed to identify and validate the pathogenic variant.

Results: The 4-year-old male proband exhibited GDD with intellectual, motor, and speech impairments. Brain MRI showed delayed myelination. WES revealed a heterozygous MAST4 missense variant (NM_001164664.2: c.4142G>T, p.Arg1381Leu), absent in population databases (gnomAD) and confirmed as de novo. The variant affects a highly conserved residue, supporting its likely pathogenicity. Phenotypic comparison with five previously reported cases confirmed core features of GDD and white matter abnormalities, though our patient lacked infantile spasms, underscoring clinical heterogeneity.

Conclusion: This study reinforces MAST4's role in NDDs and expands the genetic and phenotypic spectrum associated with this gene. The absence of infantile spasms in our case suggests variable expressivity, necessitating further functional studies to assess the variant's pathogenicity and MAST4's neurobiological mechanisms.

Keywords: MAST4; de novo variant; developmental delay; myelination dysplasia; whole-exome sequencing.

Figure 1

Brain MRI of the patient indicates myelination dysplasia. (A) T2-weighted imaging: The arrowhead denotes a region displaying abnormally persistent hyperintensity, suggesting delayed or disrupted myelination. This finding is consistent with hypomyelination, characterized by reduced myelin content and disorganized axonal maturation. (B) T1-weighted imaging: The arrow indicates a region with persistently hyperintense signal, further corroborating hypomyelination as immature white matter retains high T1 signal intensity until full myelination is achieved. The T1–T2 signal discrepancy (“T1 bright, T2 bright” paradox) is pathognomonic for developmental white matter abnormalities.

Figure 2

Sanger sequencing confirmation of the MAST4 variant. Chromatogram showing the heterozygous c.4142G>T (p.Arg1381Leu) variant in the proband (indicated by overlapping G/T peaks at position 4,142). Both parents show wild-type sequences (G/G), confirming the de novo origin of this variant.

Figure 3

Pedigree analysis of the MAST4 variant inheritance. Squares (male) and circles (female) represent family members, with filled symbols indicating affected status. The proband carries the heterozygous MAST4 p.Arg1381Leu variant (g.66438324T>C), while both unaffected parents show wild-type genotypes (“+/+”).

Figure 4

Evolutionary conservation analysis of MAST4 p.Arg1381. Multiple sequence alignment shows high arginine residue conservation at position 1,381 across vertebrate species.

Figure 5

Domain architecture of MAST4 protein showing the location of the p.Arg1381Leu variant.

Figure 6

Structural comparison of wild-type and mutant MAST4 protein at residue 1,381. (A) Wild-type MAST4 structure showing Arg1381 forming hydrogen bonds (dashed lines) with adjacent residues Ala1380 and Thr1382. (B) Mutant MAST4 (p.Arg1381Leu) structure demonstrating altered local conformation, potentially affecting protein stability or partner binding. Residue labels indicate positions 1,380–1,382 in both structures. Cyan, WT, green, mutant.