12 Matching Annotations
  1. Oct 2026
  2. www.sciencedirect.com www.sciencedirect.com
    Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
    11
    1. ClingenBaseline 24 Oct 2026
      only one variant was segregating with the disease. It revealed a homozygous premature stop mutation in NKX6-2: c.121A>T; p.Lys41∗ (NM_177400.2) in families 1 and 2. There were no other variants that segregated with the disease in these two families. Although these families are not known to be related, we found that the same homozygous truncating variant in NKX6-2 fully segregated with the disease in each family

      Families 1 and 2

      Same single variant (NKX6-2: c.121A>T; p.Lys41∗ (NM_177400.2)) segregated in both Families 1 and 2. No relation between the families.

      Haplotype analysis performed on each individual in both families which located four areas of homozygosity between each individual.

      These shared regions include 1.4M region on chromosome 10 and a haplotype block around NKX6-2 (founder effect support).

      VariantEvidence inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    2. ClingenBaseline 24 Oct 2026
      Family 1

      FamilyName: Family 1

      FamilyPresentingHPOS: HP:0001257, HP:0000639, HP:0001251

      FamilyNotHPOs:

      CountryOrigin: India

      Ethnicity: n/a

      Race: n/a

      FamilyPreviousTesting: MRI showed brain hypomyelination.

      FamilyGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

      Affected: 3

      Unaffected:

      Segregations:

      PublishedLOD:

      eLOD:

      AddSegregationInfo:

      ProbandLabel: III-1, Female, 27 yo

      Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

      ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

      gnomAD: n/a

      FamilyAddInfo:

      FamilyPMIDs:

      CaseInfo FamilyInfo inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    3. ClingenBaseline 24 Oct 2026
      Only one homozygous variant remained after application of these filters: NKX6-2 (NM_177400.2; c.487C>G; p.Leu163Val), and it fully segregated with the disease in the family under a fully penetrant autosomal-recessive model (Figure 2E). This variant was only present once in the heterozygous state in our database and is absent in ExAC

      Family 3

      Variant (NM_177400.2; c.487C>G; p.Leu163Val) fully segregated with disease, absent from ExAC, only present as heterozygous state in this study's data set.

      Variant inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    4. ClingenBaseline 24 Oct 2026
      third affected individual in this family (individual III-3) was very similar and consistent with a spastic-ataxia phenotype.

      Case#: Family 1, Individual III-3, Male, 8yo, dx at 6mo

      CasePresentingHPOs: HP:0000639, HP:0012389, HP:0001270, HP:0002078, HP:0002070, HP:0001260, HP:0007256

      CaseNotHPOs:

      CasePreviousTesting: MRI

      CaseGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

      Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

      ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

      gnomAD: n/a

      VariantEvidence:

      CaseAddInfo: Wheelchair bound at 8 yo.

      CasePMIDs:

      Individual CaseInfo inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    5. ClingenBaseline 24 Oct 2026
      Children (individuals 6 [IV-6] and 7 [IV-7]) of a third consanguineous Saudi Arabian family presented with nystagmus and developmental delay, most pronounced in the motor domain

      FamilyName: Family 3 (individuals 6 and 7)

      FamilyPresentingHPOS: HP:0000639, HP:0012736, HP:0001252, HP:0001257

      FamilyNotHPOs:

      CountryOrigin: Saudi Arabia

      Ethnicity: n/a

      Race: n/a

      FamilyPreviousTesting: MRI showed brain hypomyelination

      FamilyGenotypingMethod: combination of homozygosity mapping and WES, autozygosity mapping

      Affected: 3

      Unaffected:

      Segregations:

      PublishedLOD:

      eLOD:

      AddSegregationInfo: consanguineous family

      ProbandLabel: IV-6 (individual 6), Female, 6yo, dx at 1mo

      Variant: NM_177400.2(NKX6-2):c.487C>G (p.Leu163Val)

      ClinVar: 430623, https://www.ncbi.nlm.nih.gov/clinvar/variation/430623/

      gnomAD: n/a

      CasePresentingHPOs:

      CasePresentingHPOTerm:

      CaseNotHPOs:

      AddCaseInfo:

      VariantEvidence:

      CaseInfo FamilyInfo inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    6. ClingenBaseline 23 Oct 2026
      brother, individual 2 (III-2), has a similar but milder phenotype

      Case#: Family 1, Individual III-2, Male, 23 yo, dx at 5 years

      CasePresentingHPOs: HP:0002355, HP:0001260, HP:0001251, HP:0025402, HP:0000640, HP:0002544, HP:0012036, HP:0002451, HP:0007256

      CaseNotHPOs: HP:0100543, HP:0012547, HP:0007108

      CasePreviousTesting: MRI

      CaseGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

      Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

      ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

      gnomAD: n/a

      VariantEvidence: fibroblast cell line used to determine variant as null.

      CaseAddInfo: Walked at 12mo, but at 8yo required walking assistance. Disease did not significantly progress until teen years.

      CasePMIDs:

      Individual CaseInfo inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    7. ClingenBaseline 23 Oct 2026
      The older sibling, individual 1 (III-1)

      Case#: Family 1, Individual III-1, Female, 27 yo, dx at 3 months old

      CasePresentingHPOs: HP:0000639, HP:0001332, HP:0001270, HP:0002497, HP:0001272, HP:0002062, HP:0000571, HP:0002540, HP:0000511, HP:0012547, HP:0001260, HP:0030187, HP:0001332, HP:0000473

      CaseNotHPOs: HP:0003474, HP:0007108

      CasePreviousTesting: MRI showing brain hypomyelination

      CaseGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

      Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

      ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

      gnomAD: n/a

      VariantEvidence:

      CaseAddInfo: Wheelchair bound at 27 yo

      CasePMIDs:

      Individual CaseInfo inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    9. ClingenBaseline 22 Oct 2026
      The second family is of Kenyan and Tanzanian origin and has two affected siblings

      FamilyName: Family 2

      FamilyPresentingHPOS: HP:0002497, HP:0003429

      FamilyNotHPOs:

      CountryOrigin: Kenya and Tanzania

      Ethnicity: n/a

      Race: n/a

      FamilyPreviousTesting: MRI showed brain hypomyelination

      FamilyGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

      Affected: 2

      Unaffected:

      Segregations:

      PublishedLOD:

      eLOD:

      AddSegregationInfo:

      ProbandLabel: III-2 (individual 4), Female, 44yo, dx at 1yo

      Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

      ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

      gnomAD: n/a

      CasePresentingHPOs: HP:0000639, HP:0002066, HP:0002061, HP:0001272, HP:0007366, HP:0002540, HP:0000473, HP:0002451, HP:0002599, HP:0000571, HP:0000666, HP:0000496, HP:0002078, HP:0002070, HP:0008969, HP:0001348

      CasePresentingHPOTerm: nystagmus, gait ataxia, lower limb spasticity, cerebellar atrophy, brainstem atrophy, inability to walk, cervical dystonia, lower limb dystonia, head titubation, hypometric saccades, horizontal nystagmus, limited eye movements, truncal ataxia, limb ataxia, lower limb stiffness

      CaseNotHPOs: HP:0011730

      AddCaseInfo: Cousin with identical phenotype died due to tuberculosis in childhood. (Individual 5)

      VariantEvidence:

      CaseInfo FamilyInfo inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    10. ClingenBaseline 22 Oct 2026
      On the basis of sequence similarity and in-silico modeling, the p.Leu163Val mutation is predicted to lie within the first helix and to be protein destabilizing (DUET7 ΔΔG score: 1.418Kcal/mol). On the basis of amino acid conservation between homeodomains, the leucine residue is predicted to be highly conserved.

      Family 3

      Variant, (NM_177400.2; c.487C>G; p.Leu163Val), replaces conserved leucine within the first helix of the homeodomain, therefore destabilizing the protein.

      VariantEvidence inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
    11. ClingenBaseline 21 Oct 2026
      The c.121A>T mutation is located in exon 1 and creates a premature stop codon at amino acid 41. This stop codon is predicted to result in nonsense-mediated messenger RNA (mRNA) decay (NMD) and the loss of the homeobox functional domain.

      Families 1 and 2

      Variant, NKX6-2: c.121A>T; p.Lys41∗ (NM_177400.2), results in stop codon at amino acid 41 resulting in mRNA decay which causes the loss of the functional homeobox.

      VariantEvidence inferred_gene_hgnc:19321 inferred_gene_source:RefSeq UNC Biocuration Core
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    sciencedirect.com/science/article/pii/S0002929717301969
  3. academic.oup.com academic.oup.com
    Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy
    1
    1. ClingenBaseline 22 Oct 2026
      Family 1

      Patient Number: 1507278 Pt1

      FamilyPresentingHPOs: HP:0001583, HP:0000666, HP:0002421, HP:0002300, HP:0008947, HP:0001257, HP:0001332, HP:0011471, HP:0000543, HP:0007015, HP:0100543, HP:0000649, HP:0006958

      FamilyNotHPOs: HP:0002015

      CountryOrigin: n/a

      Ethnicity: n/a

      Race: n/a

      FamilyPreviousTesting: PLP1 mutation screening, PLP1 duplication/deletion analyses

      FamilyGenotypingMethod: Nextra custom enrichment panel, trio-based WES

      Affected: 1

      Unaffected: 2

      Segregations: consanguineous marriage

      PublishedLOD: n/a

      eLOD: n/a

      AddSegregationInfo: consanguinity

      ProbandLabel: Patient 1; II-1, male, 8 yo, dx at 2mo

      Variant: NM_177400.2; p.(Lys202Asnfs*?)

      CAID: CA658820948

      gnomAD: n/a

      FamilyAddInfo: Patient 1 born full term with no complications, disease symptoms presented at 2mo of age with nystagmus. Gastrostomy at 2 years. Required chemodenervation for dystonia. Had transitory respiratory failure or apnoeic episode at 2 years. MRI showed increased signal in anterior nucleus of thalamus, and atrophy of cerebellar vermis.

      Family FamilyInfo inferred_gene_hgnc:19321 inferred_gene_source:CAID UNC Biocuration Core
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    academic.oup.com/brain/article/140/10/2550/4085303