-associated neurodevelopmental disorder: Family with novel mutation expands the phenotypic spectrum.

Objective: Clinical, neuroimaging, and genetic characterization of 3 patients with -associated developmental regression, intellectual disability, dysmorphism, and further neurologic deficits.

Methods: Three affected brothers from a consanguineous family from Afghanistan, their 2 healthy siblings, and both parents were all assessed in the clinic. General and neurologic examination, expert dysmorphology examination, and 3T brain MRI were performed. Whole-exome sequencing was performed for the 3 affected brothers, followed by Sanger sequencing in all available family members.

Results: The index patient and his 2 affected brothers presented a complex neurologic syndrome with similar features but marked intrafamilial phenotypical variability, including varying degrees of cognitive impairment, speech impairment, dystonia, abnormal eye movements, and dysmorphic features. All 3 affected brothers are homozygous for a novel, pathogenic frameshift mutation in , c.1672_1679del, and p.Gly558Pro*22, whereas both parents and healthy siblings are heterozygous for the mutation. No major brain malformations were evident in 3T brain MRI of the affected brothers.

Conclusion: This consanguineous family with a novel mutation expands the spectrum of -associated disorder to include developmental regression, oculomotor signs, and dystonia, previously not described in the published 9 cases of this rare disorder. The 3T-MRI data from our 3 patients and review of the neuroimaging data in the literature showed unspecific brain MRI changes. LINS1 protein is a known modulating factor of the Wnt signaling pathway, with important roles in organogenesis including of the cerebral cortex. More research is warranted to disentangle the underlying pathophysiologic mechanisms, leading to cognitive impairment and the complex phenotype of -associated disorder.