Inheritance

Autosomal dominant

Prevalence

 <1 / 1 000 000

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

No ClinGen curations. Limited by Ambry and Invitae (curations from 2017 and 2019). No BabySeq. Curating variants from HGMD by prioritizing LOF.

Clinical Validity Scoring Notes and points

CHD1 encodes a chromatin remodeling protein.

• c.966G>A p.W322* - absent gnomAD v4. NMD+ (exon 18/36). Unknown if de novo.

  • PMID: 38174187

    • Patient also has NM_018489.3(ASH1L):c.1723T>G (p.Ser575Ala), but this is VUS/LB in ClinVar.

    • Phenotype consistent with PBS: 36 weeker, respiratory distress, central hypotonia. Intierstitial markings in lung. Severe hypotonia, poor feeding. Essentially normal brain MRI. There is oly a partial phenotype overlap with other cases (hypotonia). 1 point (generous)

• c.184_187delTCAG p.(Glu63Leufs*185) - Absent gnomAD, NMD+. NO POINTS

  • PMID: 38113761

    • In table S4. In patient R25912. Found to have abnormal expression in RNA. But no phenotype information provided. No evidence.

• PMID: 28866611 (PILAROWSKY PAPER) multiple variants:

  • c.1853G>A; p.Arg618Gln - DE NOVO absent gnomAD v4. Patient phenotype: DD, speech apraxia, autism, sterotypies, hypotonia, macrocephaly, immune abnormalities, depressed midface, translucent skin, allergic shiners, absence seizures, almond shaped eyes, flaring of eyebrows, downslanting-palpebral fissures, periorbital fullness, fetal finger/toepads. 1 point.

  • c.5123G>A; p.Arg1708Gln (unknown if inherited or de novo) - 6 alleles gnomAD v4, VUS in ClinVar. Found in both subject 2 and 3.

  • c.1379G>A; p.Arg460Lys - de novo. 1 allele in gnomAD. Patient with DD, hypotonia, seizures and periorbital fullness. 1 point.

  • c.421A>G, p.Arg141Gly - absent gnomAd. Inheritance unknown, in a patient with DD, speech apraxia,. , hypotonia. 0.5 points.

  • A patient with a deletion of RGMB gene and most of CHD1 had been reported, but the child didn’t have neurodevelopmental abnormalities. The authors therefore suggest the mechanism is dominant negative.

• c.5113T>C p.W1705R - absent gnomAD

  • PMID: 36625521 - de novo in patient 7 with Hypertelorism, low set ears, mild intellectual disability, developmental delay, dyskinesia, delayed speech, seizures, and congenital heart defect. Patient lymphocytes: qPCR showed mRNA expression was higher than that in controls and Western blotting showed protein expression was lower than controls. Methylation levels were higher. 294T cells: Protein expression was lower and methylation levels were higher (fig 3). 1.5 points.

• c.4550dupT p.(Leu1517Phefs*7) - NMD+ absent gnomAD.

  • Several papers in HGMD - all from autism / neurodev cohorts. None of these are likely to have a specific phenotype associated.

PMID: 28726809 - reports a recessive case with two missense variants, not consistent with inheritance. Phenotype - Microcephaly,vision impairment,absentcorpus callosum,epilepsy

Source:

Clinical Validity Points Total

5

Clinical Validity Classification

Limited.

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link