Clinical features and genomic data from the 3 individuals with partial duplications of the KDM6A gene along with variant interpretation scores
| . | Proband 1 . | Proband 2 . | Proband 3 . |
|---|---|---|---|
| Genomic data (all coordinates related to GRCh37) | |||
| tNGS Result and variant interpretation | KDM6A duplication of exons 3-26 | KDM6A duplication of exons 3-6 | KDM6A duplication of exons 2-29 |
| Uncertain | Uncertain | Uncertain | |
| WGS Result and updated variant interpretation | 163.7 kb tandem duplication mapping within KDM6A (ChrX:44,787,682–44,959,415dup) Resulting in a frameshift and premature stop codon | 117.5 kb tandem duplication mapping within KDM6A (ChrX:44,776,422–44,893,995dup) Predicted to cause an in-frame duplication | 215.8 kb tandem duplication mapping within DIPK2B (ChrX:44,799,178–45,014,969dup) Not predicted to disrupt the normal copy of KDM6A |
| Pathogenic (PVS1_very strong PS2_Strong PM2_Supporting) | VUS (PS2_Strong PM2_Supporting) | VUS (4C: 0.15 points) | |
| EPIC array analysis Result and updated variant interpretation | Not done | Consistent with KS | Inconsistent with KS |
| NA | Likely pathogenic (PS2_Strong PM2_Supporting PP4_Supporting) | VUS (4D: −0.3points) | |
| Clinical features | |||
| Sex | Male | Female | Female |
| Birth weight, g (gestational age, weeks) | 3760 (40) | 3225 (39) | 2600 (41) |
| Birth weight SDS | 0.69 | −0.23 | −2.36 |
| Age at last follow-up | 4.5 years | 3.7 years | 7.5 years |
| Age at onset of hypoglycemia | 1 day | 1 day | 3 weeks |
| Current treatment for hyperinsulinism | Diazoxide 5 mg/kg/d | None (diazoxide ∼5 mg/kg/d until aged 3.4 years) | None (diazoxide ∼4 mg/kg/d until aged 2 years) |
| Additional clinical features by the time of latest follow-up | Umbilical hernia, DD, ASD, learning difficulties, hypomobility, motor deficit, mild PVL, features consistent with KS | Mild birth asphyxia, congenital hip dislocation, mild global DD, postnatal growth delay, mild facial features | Congenital hypoplastic R-heart syndrome, birth asphyxia, global DD, autism |
| . | Proband 1 . | Proband 2 . | Proband 3 . |
|---|---|---|---|
| Genomic data (all coordinates related to GRCh37) | |||
| tNGS Result and variant interpretation | KDM6A duplication of exons 3-26 | KDM6A duplication of exons 3-6 | KDM6A duplication of exons 2-29 |
| Uncertain | Uncertain | Uncertain | |
| WGS Result and updated variant interpretation | 163.7 kb tandem duplication mapping within KDM6A (ChrX:44,787,682–44,959,415dup) Resulting in a frameshift and premature stop codon | 117.5 kb tandem duplication mapping within KDM6A (ChrX:44,776,422–44,893,995dup) Predicted to cause an in-frame duplication | 215.8 kb tandem duplication mapping within DIPK2B (ChrX:44,799,178–45,014,969dup) Not predicted to disrupt the normal copy of KDM6A |
| Pathogenic (PVS1_very strong PS2_Strong PM2_Supporting) | VUS (PS2_Strong PM2_Supporting) | VUS (4C: 0.15 points) | |
| EPIC array analysis Result and updated variant interpretation | Not done | Consistent with KS | Inconsistent with KS |
| NA | Likely pathogenic (PS2_Strong PM2_Supporting PP4_Supporting) | VUS (4D: −0.3points) | |
| Clinical features | |||
| Sex | Male | Female | Female |
| Birth weight, g (gestational age, weeks) | 3760 (40) | 3225 (39) | 2600 (41) |
| Birth weight SDS | 0.69 | −0.23 | −2.36 |
| Age at last follow-up | 4.5 years | 3.7 years | 7.5 years |
| Age at onset of hypoglycemia | 1 day | 1 day | 3 weeks |
| Current treatment for hyperinsulinism | Diazoxide 5 mg/kg/d | None (diazoxide ∼5 mg/kg/d until aged 3.4 years) | None (diazoxide ∼4 mg/kg/d until aged 2 years) |
| Additional clinical features by the time of latest follow-up | Umbilical hernia, DD, ASD, learning difficulties, hypomobility, motor deficit, mild PVL, features consistent with KS | Mild birth asphyxia, congenital hip dislocation, mild global DD, postnatal growth delay, mild facial features | Congenital hypoplastic R-heart syndrome, birth asphyxia, global DD, autism |
Duplications are reported according to NM_021140.3 with genomic coordinates listed according to GRCh37.
Variant classification using (23-25): PVS1_very strong: Duplication proven in tandem, reading frame disrupted, and nonsense-mediated decay predicted to occur. PS2_Strong: Confirmed de novo. PM2_Supporting: absent from population databases. PP4_Supporting: Patients phenotype is highly specific for the disease (episignature confirmed by methylation analysis). 4C: de novo, 4D: the reported phenotype (episignature confirmed by methylation analysis) is not consistent with the gene.
Abbreviations: ASD, autism spectrum disorder; DD, developmental delay; GA, gestational age; GRCh37, Genome Reference Consortium Human Build 37; KS, Kabuki syndrome; PVL, periventricular leukomalacia; NA, not applicable; SDS, SD score; tNGS, targeted next-generation sequencing; VUS, variant of unknown significance; WGS, whole genome sequencing.
Clinical features and genomic data from the 3 individuals with partial duplications of the KDM6A gene along with variant interpretation scores
| . | Proband 1 . | Proband 2 . | Proband 3 . |
|---|---|---|---|
| Genomic data (all coordinates related to GRCh37) | |||
| tNGS Result and variant interpretation | KDM6A duplication of exons 3-26 | KDM6A duplication of exons 3-6 | KDM6A duplication of exons 2-29 |
| Uncertain | Uncertain | Uncertain | |
| WGS Result and updated variant interpretation | 163.7 kb tandem duplication mapping within KDM6A (ChrX:44,787,682–44,959,415dup) Resulting in a frameshift and premature stop codon | 117.5 kb tandem duplication mapping within KDM6A (ChrX:44,776,422–44,893,995dup) Predicted to cause an in-frame duplication | 215.8 kb tandem duplication mapping within DIPK2B (ChrX:44,799,178–45,014,969dup) Not predicted to disrupt the normal copy of KDM6A |
| Pathogenic (PVS1_very strong PS2_Strong PM2_Supporting) | VUS (PS2_Strong PM2_Supporting) | VUS (4C: 0.15 points) | |
| EPIC array analysis Result and updated variant interpretation | Not done | Consistent with KS | Inconsistent with KS |
| NA | Likely pathogenic (PS2_Strong PM2_Supporting PP4_Supporting) | VUS (4D: −0.3points) | |
| Clinical features | |||
| Sex | Male | Female | Female |
| Birth weight, g (gestational age, weeks) | 3760 (40) | 3225 (39) | 2600 (41) |
| Birth weight SDS | 0.69 | −0.23 | −2.36 |
| Age at last follow-up | 4.5 years | 3.7 years | 7.5 years |
| Age at onset of hypoglycemia | 1 day | 1 day | 3 weeks |
| Current treatment for hyperinsulinism | Diazoxide 5 mg/kg/d | None (diazoxide ∼5 mg/kg/d until aged 3.4 years) | None (diazoxide ∼4 mg/kg/d until aged 2 years) |
| Additional clinical features by the time of latest follow-up | Umbilical hernia, DD, ASD, learning difficulties, hypomobility, motor deficit, mild PVL, features consistent with KS | Mild birth asphyxia, congenital hip dislocation, mild global DD, postnatal growth delay, mild facial features | Congenital hypoplastic R-heart syndrome, birth asphyxia, global DD, autism |
| . | Proband 1 . | Proband 2 . | Proband 3 . |
|---|---|---|---|
| Genomic data (all coordinates related to GRCh37) | |||
| tNGS Result and variant interpretation | KDM6A duplication of exons 3-26 | KDM6A duplication of exons 3-6 | KDM6A duplication of exons 2-29 |
| Uncertain | Uncertain | Uncertain | |
| WGS Result and updated variant interpretation | 163.7 kb tandem duplication mapping within KDM6A (ChrX:44,787,682–44,959,415dup) Resulting in a frameshift and premature stop codon | 117.5 kb tandem duplication mapping within KDM6A (ChrX:44,776,422–44,893,995dup) Predicted to cause an in-frame duplication | 215.8 kb tandem duplication mapping within DIPK2B (ChrX:44,799,178–45,014,969dup) Not predicted to disrupt the normal copy of KDM6A |
| Pathogenic (PVS1_very strong PS2_Strong PM2_Supporting) | VUS (PS2_Strong PM2_Supporting) | VUS (4C: 0.15 points) | |
| EPIC array analysis Result and updated variant interpretation | Not done | Consistent with KS | Inconsistent with KS |
| NA | Likely pathogenic (PS2_Strong PM2_Supporting PP4_Supporting) | VUS (4D: −0.3points) | |
| Clinical features | |||
| Sex | Male | Female | Female |
| Birth weight, g (gestational age, weeks) | 3760 (40) | 3225 (39) | 2600 (41) |
| Birth weight SDS | 0.69 | −0.23 | −2.36 |
| Age at last follow-up | 4.5 years | 3.7 years | 7.5 years |
| Age at onset of hypoglycemia | 1 day | 1 day | 3 weeks |
| Current treatment for hyperinsulinism | Diazoxide 5 mg/kg/d | None (diazoxide ∼5 mg/kg/d until aged 3.4 years) | None (diazoxide ∼4 mg/kg/d until aged 2 years) |
| Additional clinical features by the time of latest follow-up | Umbilical hernia, DD, ASD, learning difficulties, hypomobility, motor deficit, mild PVL, features consistent with KS | Mild birth asphyxia, congenital hip dislocation, mild global DD, postnatal growth delay, mild facial features | Congenital hypoplastic R-heart syndrome, birth asphyxia, global DD, autism |
Duplications are reported according to NM_021140.3 with genomic coordinates listed according to GRCh37.
Variant classification using (23-25): PVS1_very strong: Duplication proven in tandem, reading frame disrupted, and nonsense-mediated decay predicted to occur. PS2_Strong: Confirmed de novo. PM2_Supporting: absent from population databases. PP4_Supporting: Patients phenotype is highly specific for the disease (episignature confirmed by methylation analysis). 4C: de novo, 4D: the reported phenotype (episignature confirmed by methylation analysis) is not consistent with the gene.
Abbreviations: ASD, autism spectrum disorder; DD, developmental delay; GA, gestational age; GRCh37, Genome Reference Consortium Human Build 37; KS, Kabuki syndrome; PVL, periventricular leukomalacia; NA, not applicable; SDS, SD score; tNGS, targeted next-generation sequencing; VUS, variant of unknown significance; WGS, whole genome sequencing.
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