Expanding the clinical and genetic spectra of NKX6-2-related disorder
C Baldi 1, A M Bertoli-Avella 1, N Al-Sannaa 2, M Alfadhel 3, K Al-Thihli 4, S Alameer 5, A A Elmonairy 6, A M Al Shamsi 7, H A Abdelrahman 8, L Al-Gazali 9, A Shawli 5 10, F Al-Hakami 10 11, H Yavuz 1, K K Kandaswamy 1, A Rolfs 1 12, O Brandau 1, P Bauer 1
Affiliations
Affiliations
- Centogene AG, Rostock, Germany.
- John Hopkins Aramco Health Care, Pediatric Services, Dhahran, Saudi Arabia.
- King Abdullah International Medical Research Centre, King Saud Bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (NGHA), Riyadh, Saudi Arabia.
- Department of Genetics, Sultan Qaboos University Hospital, Muscat, Oman.
- King Saud Bin Abdulaziz University for Health Sciences, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (NGHA), Jeddah, Saudi Arabia.
- Kuwait Medical Genetics Center, Kuwait.
- Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University Al Ain, Al-Ain, United Arab Emirates.
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University Al Ain, United Arab Emirates.
- Molecular Medicine Section, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
- Molecular Medicine Section, King Abdulaziz Medical City-WR, Jeddah, Saudi Arabia.
- Albrecht-Kossel-Institute for Neuroregeneration, Medical University Rostock, Rostock, Germany.
Abstract
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.
Keywords: NKX6-2; autosomal recessive inheritance; hypomyelinating leukodystrophy; white-matter changes.
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