Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Mentioned in ClinGen Intellectual Disability curation. GenCC - Strong by Ambry. Not in BabySeq curation. Reviewed the LOF HGMD variants below:

Clinical Validity Scoring Notes and points

c.1527C>G p.Y509* - PMID: 28191890 and 34312540 - two large autism / neurodevelopmental disorder papers, both list variant in supplement per HGMD comment, skipping for now.

Gene is pLOF constrained, LOEUF =0.3

LOF VARIANTS:

Pennings 2020 PMID:31488895 - Exome sequencing performed in heredtiary spastic paraplegia cohort from Netherlands.

1. NM_004321.6(KIF1A):c.3975C>G p.Y1325* - Absent gnomAD, NMD+, LP in ClnVar by 1 submitter. PMID: 31488895 - Autosomal dominant hereditary spastic paraplegia. Inherited and segregates in 2 affected family members per fig 2. 2 points

2. NM_004321.6(KIF1A): c.1867C>T;p.(Gln623*) - in P16, inherited from affected parent. 2 points

3. NM_004321.6(KIF1A): c.4096_4103dup; p.(Asp1369Profs*17 - absent gnomAD, NMD+. Autosomal dominant hereditary spastic paraplegia. Inherited from affected parent in family P21, see fig 2. Onset at 2y. 2 points

4. NM_004321.6(KIF1A): c.4740dupG p.(Tyr1581Valfs*50) - absent gnomAD, NMD+. AD hereditary spastic paraplegia, de novo in family P23 see fig 2. Onset <5y. 2 points

5. NM_004321.6(KIF1A): c.4292delC p.(Pro1431Argfs*67) - absent gnomAD, NMD+. AD hereditary spastic paraplegia, inherited from affected parent in family P22 see fig 2. 1 seg. Onset 2y. 2 points

6. whole gene deletion, de novo in proband from P24 (AD HSP). Onset at 1. 2 points

Vecchia 2022 PMID: 34487232 NM_004321.6(KIF1A):c.28delG p.(Val10Cysfs*11) - absent gnomAD, found in a patient with hereditary spastic paraplegia. Per supplement, the variant was in patient 4. Unclear if variant inherited or de novo, de novo codes were not applied using ACMG criteria. 2 points

PMID: 31512412 - c.275_276insAA p.(Cys92*) - de novo variant found in a girl with features of Rett syndrome: Developmental delay, Did not achieve independent ambulation and absent speech at 13 months of age. Microcephaly. Hand clapping and mouthing, loss of hand skills, grinding teeth, breathing, and sleeping disturbance appeared around 8 months of age. Brain MRI was normal.

Clinical Validity Points Total

14 points

Clinical Validity Classification

Clinical Validity Points Total

14 points

Clinical Validity Classification

Strong

PMID: 31488895

Molecular Mechanism

Loss of function - see Scoring Notes and PoInts above for details.

PMID: 31488895, 34487232

Penetrance

(list source/PMID)

Unknown

Source:

Age of Onset

(list source/PMID)

Childhood - adulthood

PMID: 31488895

Severity

Moderate

Clinical Features

Slowly progressive hereditary spastic paraplegia, typically without any additional clinical features such as cognitive deficits.

Sources: 31488895

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 variantSEE ABOVE

Curation Summary

SEE ABOVE

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 11.28.2023 D-190115360-BH-4000-P-A

Inheritance

Autosomal recessive

Prevalence

Source:

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Mentioned in ClinGen Intellectual Disability curation. GenCC - Limited by Ambry

Clinical Validity Scoring Notes and points

Ghafoor 2022 PMID: 36282036 - NM_004321.8:c.2658delC p.(Val887Serfs*89) (not in the alternatively spliced exon- article requested and saved in our publication library. Absent gnomAD, NMD+. Per abstract, SNP analysis to find ROH followed by exome identified the variant in a family with severe manifestations of HSAN. Severe phenotype included developmental delay, hypoalgesia, decreased temperature sensation, dryness of skin which observed in individuals of the family, ulceration of limbs at the age of eight years with subsequent amputation. Het carriers did not have neuropathy symptoms, but had scaly skin. 2 POINTS

Riviere 2011 PMID: 21820098 - Homozygosity mapping followed by KIF1A sequencing in Afghan family, then testing in 112 additional unrelated HSAN cases.

• NM_001244008.1:c.2840delT Leu947Argfs*4 (exon 27, alternatively spliced)- (0.001%, 17/1147050 European chr) - homozygous in 3 unrelated families with hereditary sensory neuropathy (Afghan, Turkish, and 2 Belgian families). Parents were not all phased; could potentially score 3 segregations from family 1 and 2 but given consanguinity decided against it. Phenotype description - numbness in feet and hands, ulcerative lesions developed and resulted in amputation, normal mental state/cranial nerves, pinprick and touch senses normal but vibration impaired in feet and hands. Exon 25b is an alternatively spliced exon. 2 POINTS (ALT EXON)

• NM_001244008.1:c.5271dupC p.(Ser1758Glnfs*7) (NMD- in exon 48, absent gnomAD, P in ClinVar by OMIM)- compound het in trans with c.2840delT Leu947Argfs*4 in family 4 per fig 4. 1 POINTS

• Experimental data

  • Yeast 2 hybrid screen used to identify proteins that interact with HSN2 exon of WNK1, positive clone identified corresponded to KIF1A. Separate interaction assays between the HSN2 exon and fragments of KIF1A identified 3 segments of overlap including the alternate exon 25b aka ex27 in NM_001244008.1 (fig 1) - 1 POINT PROTEIN INTERACTION

  • RT-PCR with human RNA samples observed that the alternate exon 25b aka ex27 was strongly expressed in the nervous system. But the isoform lacking this exon was the most abundant form in adult brain and DRG. (fig 5). Expression 1 POINT

  • Silencing of KIF1A in mouse DRG using lentiviral delivery of shRNAs substantially reduced KIF1A in cell bodies but did not reduce WNK1/HSN in axons suggesting that there are other transporters of WNK1/HSN. Not scoring points.

PMID: 31734026

• NM_001244008.2:c.3871C>T p.R1291C - MAF seems too high 0.1%, 69/43308 East Asian chr in gnomAD v4, did not review papers further. Found in a patient with NM_001244008.2:c.3898G>A p.V1300M - 0.05% 33/42690 East Asian chr in gnomAD v4, REVEL 0.523 found in cohort of patients with SMA like symptoms. Walking disturbance, plantar sensory loss PER TABLE 2. Found via sanger per text. Not scoring either variant due to MAF.

Clinical Validity Points Total

7 points

Clinical Validity Classification

Moderate

Molecular Mechanism

Unknown, LOF suspected, but due to alternately spliced exon, not certain

2 NMD+ variants and one NMD-

1. c.2658delC p.(Val887Serfs*89)

2. c.2840delT Leu947Argfs*4 (alternate exon)

3. c.5271dupC p.(Ser1758Glnfs*7) - penultimate exon.

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Severity

Clinical FeaturesSources:

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 variantSEE ABOVE

Curation Summary

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 11.28.2023 D-190115360-BH-4000-P-A