DONSON-Associated MISSLA with Co-Occurring p.Arg442Ter and p.Lys489Thr Variants: Longitudinal Clinical and Genomic Characterization

Background: Microcephaly, short stature, and limb abnormalities syndrome (MISSLA) is an ultra-rare developmental disorder associated with biallelic DONSON variation and characterized by prenatal-onset growth restriction, congenital microcephaly, variable skeletal abnormalities, and neurodevelopmental impairment. We describe the longitudinal clinical and genomic features of an Ecuadorian child with a phenotype highly compatible with DONSON-associated MISSLA. Methods: This retrospective longitudinal case report included clinical information from the prenatal period through February 2026. Serial anthropometric, neurodevelopmental, nutritional, skeletal, and neuroimaging findings were reviewed. Clinical whole-exome sequencing with mitochondrial DNA analysis was performed during infancy. DONSON variants were evaluated using current transcript nomenclature, population and clinical databases, and published variant-specific evidence. Because patient-derived RNA was unavailable, the predicted susceptibility of NM_017613.4:c.1324C>T (p.Arg442Ter) to nonsense-mediated mRNA decay (NMD) was assessed using NMDetective-B. Results: The proband had severe prenatal growth restriction and congenital microcephaly, followed by persistent profound short stature, marked postnatal weight impairment, feeding difficulties, developmental delay with continued acquisition of motor and language abilities, and relatively mild skeletal involvement. At 7 years and 4 months, weight was 10.3 kg (Z = −8.02) and height was 91.5 cm (Z = −5.00). Whole-exome sequencing identified heterozygous DONSON c.1324C>T (p.Arg442Ter) and c.1466A>C (p.Lys489Thr), together with c.82A>C (p.Ser28Arg). The recurrent intronic c.786-33A>G variant was not detected, although limited coverage precluded definitive exclusion. Parental segregation data were unavailable, and compound heterozygosity was therefore not established. NMDetective-B yielded a score of 0.65, predicting that p.Arg442Ter is susceptible to NMD. Conclusions: This case extends the longitudinal phenotypic characterization of DONSON-associated MISSLA and documents a distinct co-occurring variant configuration. The NMD result provides a testable transcript-level hypothesis for p.Arg442Ter, but the absence of parental phasing and patient-derived RNA or protein studies precludes definitive assignment of a patient-specific molecular mechanism.