SLC12A2 Gene Curation

Gene-disease assertions not curated here (add link or write note): did not curate the AD hearing loss phenotype, but note that these variants cluster to exon 21, and Exon 21 containing isoform the only transcript in the developing cochlea (McNeill et al., 2020).

Disease	Kilquist syndrome
Inheritance	Autosomal recessive
Prevalence Possible sources Orphanet Medline Plus Genetics	Source:
Rapid or full curation?	Rapid 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	AR Kilquist syndrome PMID: 34797034 reports child with respiratory distress, thick secretions in the airway, midgut malrotation and GERD. Recurrent staph infection. Global DD, severe-profound bilateral sensorineural hearing loss. Two variants in trans: c.1536+4_1536+7del (RNA seq showed del exons 8 and 9) and c.940C>T p.Q314* (https://gnomad.broadinstitute.org/variant/5-128114275-C-T?dataset=gnomad_r4 , 2 alleles, NMD+) 2x2 LOF POINTS = 4 VARIANT POINTS No phenotype in the heterozygous parents. Supports LOF is mechanism for AR only. Authors propose that the heterozygous de novo syndrome described in severe neurodev patients from McNeill et al., 2020 might be due to a dominant negative effect Table 1 also summarizes additional AR cases: Stodberg 1 (PMID: 32754646)- c.1431delT (Phe477Leufs48) and 2006-1G>A and sibling with the same variants. Both considered LOF. 2 x 2 LOF variants = 4 points* Kilquist (Macnamara et al 2019 PMID: 30740830) - 22 kb deletion (exons 2-6) and UPD (ie - results in a 22kb deletion) 2x2 LOF variants = 4 points. Bilal Shamshi family 1 and 2 (PMID: 33500540) - per the original paper, both families have homozygous c.2617-2A>G. Parents confirmed het carriers. Counting 1 proband in case of shared ancestry, 2x2 LOF = 4 POINTS + 2 AR SEGREGATIONS Experimental NKCC1 has been demonstrated to play a central role in neurogenesis and the excitatory-inhibitory GABA switch (Delpire et al., 1999) PMID: 10369265 32658972 - Analysis of SLC12A2 expression in foetal brain at 16-18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. 1 POINT EXPRESSION 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	>12 Source:
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Definitive (replicated 2019-2021) Source: 34797034, 32754646, 30740830, 33500540
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function See clinical validity scoring, all LOF PMID: 34797034, 32754646, 30740830, 33500540
Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID)
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)	Congenital
Severity Options 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	PMID: 34797034 reports child with respiratory distress, thick secretions in the airway, midgut malrotation and GERD. Recurrent staph infection. Global DD, severe-profound bilateral sensorineural hearing loss. Additional features table 1: microcephaly abnormal brain MRI (basal ganglia injury, reduced cerebral volume, white matter hyperintensity Sources: 34797034
HPO Terms https://hpo.jax.org/app/
Gene SOPs & Notes
Curation Summary Examples - 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

Disease	Delpire-McNeill syndrome
Inheritance	Autosomal dominant
Prevalence Possible 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.(Val1026Phefs2) - PMID: 37399495 / 27900370* - It looks like these paper report the same individual but nomenclature is incorrect in PMID: 37399495, reporting patient from UDN program with 5:127514355, 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 Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Source:
Molecular Mechanism Mechanisms 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 options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID)	Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)
Severity Options 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 Examples 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

SLC12A2 Gene Curation

Kilquist syndrome

Delpire-McNeill syndrome