Expanding the clinical and genetic spectra of NKX6-2-related disorder

C. Baldi, A. M. Bertoli-Avella, N. Al-Sannaa, M. Alfadhel, K. Al-Thihli, S. Alameer, A. A. Elmonairy, A. M. Al Shamsi, H. A. Abdelrahman, L. Al-Gazali, A. Shawli, F. Al-Hakami, H. Yavuz, K. K. Kandaswamy, A. Rolfs, O. Brandau, P. Bauer

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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 3 and 2 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 they show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in 2 families each) represent an addition to the phenotype, while developmental regression (observed in 3 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.

Original languageEnglish
Pages (from-to)1087-1092
Number of pages6
JournalClinical Genetics
Issue number5
Publication statusPublished - May 2018


  • NKX6-2
  • autosomal recessive inheritance
  • hypomyelinating leukodystrophy
  • white-matter changes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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