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Disease

Delpire-McNeill syndrome

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

  •  Rapid - determine if LOF is mechanism
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

No ClinGen Curations, 3 strong curations from Invitae (AD hearing loss, AD Delpire-McNeill syndrome, AR Kilquist syndrome)

Clinical Validity Scoring Notes and points

PMID: 32658972 - cohort study

  • c.980C>T p.Ala327Val - de novo in case 1

    • iris coloboma, ventricular septal defect and tracheo-oesophageal fistula, microcephaly, bilateral sensorineural deafness, developmental delay cortical dysplasia

  • c.1229G>A Arg410Gln - de novo in case 2

    • autism, mild ID

  • c.2675G>A Trp892* - de novo in case 3

    • golbal DD, autism, motor sterotypy, hypotonia, bilateral SNHL, non-verbal.

  • c.1127A>T Asn376Ile - de novo in case 4

    • spastic paraparesis, delay of speech and gross motor development,

  • c.555dupG His186AlafsTer17 - de novo in case 5

    • severe global DD, swallowing difficulties, muscle hypertonia, hip dislocation, thoracolumbar scoliosis, doesn’t walk independently, non verbal, agenesis of the corpus callosum

  • c.1135_1136delGCinsCT p.(Ala379Leu) - de novo in case 6

    • Autism, ID, delayed language acquisition.

  • c.2938G>A p.E980K De novo in case 7

    • hypotonia, tongue fasciculation and developmental delay, bilateral sensorineural hearing impairment, nystagmus, tongue fasciculations.

  • c.2935G>A p.E979K - in family members case 8 and 9.

    • BNSHL with bilateral congenital vestibular areflexia with dominant pattern of inheritance

  • All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes

c.3076_3086del11 p.(Val1026Phefs*2) - PMID: 37399495 / 27900370 - It looks like these paper report the same individual but nomenclature is incorrect in PMID: 37399495, reporting patient from UDN program with5:127514355, ATGTCTGGTGGC > A leading to p.V1226Ffs2. obstructive apnea, vomiting, dehydration, decreased energy and fatigue, exercise intolerance, left ventricular dilated myopathy, and seizure-like symptoms. Variant was coinjected into Xenopus oocytes, showed totoal absence of function, no evidence of dominant negative effect. We demonstrated that the wild-type NKCC1 transporter trafficked properly to the basolateral membrane as expected, but surprisingly, the mutant transporter mis-trafficked to the apical membrane. More intriguing was the discovery that the mutant transporter could, likely through dimerization, send some wild-type transporters to the apical membrane (16). Thus, this mistargeting constitutes a significant dominant negative effect in epithelial cells. Further research revealed that the mis-trafficking was due to the loss of a di-leucine-like motif at the extreme end of the protein. Supports dominant negative effect?

PMID:

Experimental

  • NKCC1 has been dem-onstrated to play a central role in neurogenesis and the excitatory-inhibitory GABA switch (Delpire et al., 1999)

  • Exon 21 containing isoform the only tran-script in the developing cochlea (McNeill et al., 2020), which is likely why exon 21 variants cause nonsyndromal deafness and variants in other exons cause a more severe neurdeve disorder.

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown - possibly dominant negative

Notes:

  • Per PMID: 34797034 describing AR Kilquist syndrome, none of the parents appeared to be affected, all carried LOF variants. Evidence against LOF for the AD Delpire-McNeill syndrome.

  • 3 patients w/ LOF variants and AD Delpire-McNeill syndrome (PMID: 32658972, 37399495), phenotype isn’t very specific. See clinical validity scoring. In PMID: 37399495 they describe experiments that hint towards a dominant negative mechanism. Gene encodes a transporter that forms a dimer, so a DN effect could make sense.

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

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titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

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

Expand
titleExamples

  • The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

  • Variable expression or severity:


The severity and expressivity of the disorder is highly variable, even within families.

  • If multiple conditions associated with the gene:


It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

  • Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link

Andrea Oza E3800892000, 09.23.24