Expanding the Clinical and Genetic Spectra of NKX6-2-Related Disorder

Clin Genet. 2018 Feb 1. doi: 10.1111/cge.13221. [Epub ahead of print]


Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system, and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6-2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole exome or whole genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6-2 in three and two unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients share a primary diagnosis of psychomotor delay, and show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in two families each) represent an addition to the phenotype, while developmental regression (observed in three families) appears to be a notable and previously underestimated clinical feature. Our findings extend the clinical and mutational spectra associated with this novel form of HLD. Comparative analysis of our 10 patients and the 15 reported previously did, however, not reveal clear evidence for a genotype-phenotype correlation.


  • Caterina Baldi , PhD
  • Aida M. Bertoli-Avella , MD
  • Nouriya Al-Sannaa
  • Majid Alfadhel , MD
  • K Al-Thilhi
  • S Alameer
  • A.A. Elmonairy
  • AM Al Shamsi
  • H.A. Abdelrahman
  • L Al-Gazali
  • A. Shawli
  • F Al Hakami
  • Halenur Yavuz
  • Krishna Kumar Kandaswamy , PhD
  • Prof. Arndt Rolfs , MD
  • Oliver Brandau , MD
  • Dr. Peter Bauer , MD

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