Clinical characteristics.

KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic neuropathy, poor weight gain, and neurobehavioral issues including autism spectrum disorder. Manifestations most commonly appear in early childhood but may be detected as early as the neonatal period. There is significant phenotypic heterogeneity.

Diagnosis/testing.

The diagnosis of KIF1A-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant or, less commonly, biallelic pathogenic variants in KIF1A identified by molecular genetic testing.

Management.

Supportive treatment: Multidisciplinary care by specialists in education of children with developmental delay / intellectual disability; management of seizures and pain associated with peripheral neuropathy by neurologist; management by orthopedist, physical medicine and rehabilitation specialist, or occupational therapist for fine motor development; physical therapy including stretching to help avoid contractures and falls; feeding therapy to manage dysphagia; treatment by ophthalmologist to manage refractive errors; speech-language therapy to improve communication.

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, regularly scheduled evaluations by treating clinicians are recommended.

Genetic counseling.

KIF1A-NDD can be inherited in an autosomal dominant or, less commonly, autosomal recessive manner.

Autosomal dominant inheritance: Most individuals diagnosed with autosomal dominant KIF1A-NDD have the disorder as the result of a de novo pathogenic variant. Some individuals diagnosed with KIF1A-NDD have an affected parent. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the KIF1A pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism.

Autosomal recessive inheritance: If both parents are known to be heterozygous for a KIF1A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of the KIF1A pathogenic variants in the family.

Once the KIF1A pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

KIF1A-NDD should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

• Developmental delay / intellectual disability
• Feeding difficulties
  • Neonatal feeding difficulties / poor suck
  • Poor oral motor coordination
• Growth abnormalities
  • Short stature
  • Microcephaly (congenital or acquired)
• Neurologic problems
  • Hypotonia (often the first presenting manifestation, typically occurring in the first year of life)
  • Hypertonia
  • Excessive clumsiness / coordination disorder
  • Peripheral neuropathy
• Motor impairment
  • Dystonia
  • Hyperkinetic movement disorder (stereotypic movements, tics, dystonia)
  • Ataxia
  • Dysarthria
• Visual impairment
  • Optic nerve atrophy
  • Cerebral visual impairment
  • Cataracts
• Epilepsy
  • Age of onset is typically in childhood; however, some individuals have their first seizure in adolescence.
  • Multiple seizure types are observed.
• Neurobehavioral/psychiatric manifestations
  • Autism spectrum disorder
  • Attention-deficit/hyperactivity disorder
  • Sleep difficulties
  • Obsessive-compulsive disorder, depression, anxiety, psychosis (typically occurring in adolescence)

Brain MRI findings

• Cerebral and cerebellar atrophy (often progressive)
• Corpus callosum hypoplasia or atrophy

Family history. Because KIF1A-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations) or autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity).

Establishing the Diagnosis

The diagnosis of KIF1A-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant or biallelic pathogenic (or likely pathogenic) variants in KIF1A identified by molecular genetic testing (see Table 1) [Boyle et al 2021, Sudnawa et al 2024].

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a KIF1A variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include use of a multigene panel.

Note: Single-gene testing (sequence analysis of KIF1A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used, and yields results similar to an intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. To date, the majority of KIF1A pathogenic variants reported are within the coding region and are likely to be identified on exome sequencing. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• A multigene panel that includes KIF1A and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic chromosome microarray while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, progressive spastic paraplegia, peripheral and autonomic neuropathy, autism spectrum disorder, and optic nerve atrophy [Boyle et al 2021]. There is significant phenotypic heterogeneity. Manifestations most commonly appear in early childhood but may be detected as early as the neonatal period.

To date, about 300 individuals with KIF1A-NDD have been identified [Nemani et al 2020, Pennings et al 2020, Boyle et al 2021, Nicita et al 2021, Vecchia et al 2022, Paprocka et al 2023, Sudnawa et al 2024]. The following description of the phenotypic features associated with KIF1A-NDD is based on these reports.

Developmental delay / intellectual disability

• Some form of developmental delay is observed in more than 90% of individuals
• Regression and cognitive decline are common, especially in those with epilepsy; however, the age of onset of regression and the rate of decline vary.

Speech and language issues

• Receptive language is often stronger than expressive language; social communication may be impaired.
• Dysarthria is common, with some studies showing some degree of impairment in all assessed individuals [Morison et al 2026].

Infant feeding difficulties are common. While most individuals can eat by mouth, some require placement of a gastrostomy tube, typically due to problems with aspiration.

Neurobehavioral/psychiatric manifestations

• Manifestations of sleep difficulties are seen in ~45% of individuals. These can include atypical sleep-wake cycles, difficulties falling asleep, frequent awakening during the night, and individuals who go for more than 24 hours without sleeping.
• Common challenging behaviors can include stereotypies, repetitive behaviors, aggressive behaviors, and self-injurious behaviors.
• Autism spectrum disorder is observed in ~25% of individuals.
• Attention-deficit/hyperactivity disorder is observed in ~25% of individuals, though many have issues with hyperactivity even in the absence of this diagnosis.
• Anxiety and obsessive-compulsive disorder are the most common psychiatric comorbidities.
• Depression, bipolar disorder, and psychosis are common, especially starting in adolescence and adulthood.

Motor impairment and neurologic features

• Hypotonia is seen in ~86% of individuals. It is often the first presenting manifestation, typically occurring in the first year of life.
• Hypertonia/spasticity, seen in ~80% of individuals, often co-occur with hypotonia. Frequently, truncal hypotonia is accompanied by lower extremity hypertonia.
• Excessive clumsiness / coordination disorder is reported in ~60% of individuals.
• Hyperkinetic movement disorder (e.g., stereotypic movements and tics) is reported in ~20% of individuals.
  • Ataxia, in 28% of individuals, is associated with increased falls and injuries.
  • Tremors, in 22% of individuals, can limit fine motor function.
  • Dystonia, in 15% of individuals, can result in pain or instability.
• Peripheral neuropathy, reported in ~30% of individuals, is likely underestimated. Manifestations vary but can include pain, paresthesia, or sensory loss.
• Autonomic dysfunction appears to be relatively common, with many individuals having poor circulation (e.g., skin mottling, cold feet) and some having difficulties with temperature regulation.

Neuroimaging

• In addition to the characteristic findings described in Suggestive Findings, many nonspecific neuroimaging abnormalities are observed, including diffuse or nonspecific cerebral atrophy in many individuals or localized findings (e.g., frontal lobe-specific volume loss or cortical thinning).
• Periventricular leukomalacia, described as an early finding, has resulted in a misdiagnosis of static cerebral palsy.

Epilepsy is seen in ~40% of individuals

• While age of onset is typically in childhood (median age of onset: 3.3 years), some individuals have their first seizure in adolescence.
• Multiple seizure types are observed. Absence seizures are the most common, followed by grand mal seizures, atonic or drop seizures, and infantile spasms. Some individuals have specific seizure disorders such as electrical status epilepticus in sleep or Lennox-Gastaut syndrome. One person can have multiple different seizure types and frequency throughout the course of their life.
• Seizure frequency can vary. Roughly one third of individuals with epilepsy have daily seizures, whereas some individuals have only one or two seizures in their lifetime.
• EEG abnormalities can be observed even in individuals without clinical seizures.

Visual impairment

• Refractive errors are common: 47% have either myopia or hyperopia with 14% having amblyopia.
• Optic nerve hypoplasia is occasionally present. Optic nerve atrophy and degeneration will eventually occur in almost all individuals and is likely underreported. While large-scale surveys report optic nerve atrophy in close to 50% of affected individuals, one study comparing caregiver-reported diagnoses of optic atrophy and a comprehensive in-person evaluation found evidence of atrophy in 20 of 22 individuals despite it having been previously reported in only 10 of the 22 [Sudnawa et al 2024].
• Cerebral visual impairment and strabismus are both seen in close to one third of individuals.
• Nystagmus is seen in 22% of individuals.
• Cataracts are seen in ~10% of individuals.
• Although rarely reported, deficits in color vision, visual fields, and depth perception appear to be common when specifically evaluated.

Growth

• Although most individuals with KIF1A-NDD have typical growth, short stature is seen in ~16% of individuals. Growth hormone deficiency is rarely observed.
• Microcephaly can be congenital or acquired.

Musculoskeletal

• Scoliosis was reported in 14% of individuals in one study, but as most study participants were relatively young (mean age: 9.9 years; median age: 7.3 years), this may be an underrepresentation as the cohort gets older [Boyle et al 2021].
• Contractures, seen in 10% of individuals, most commonly involve hips, ankles, fingers, and toes.
• Although fractures are seen in 26% of individuals, this is likely related at least in part to the excessive clumsiness common in these individuals.

Gastrointestinal difficulties

• Gastroesophageal reflux disease is seen in 34% of individuals.
• Other findings include constipation (40%), diarrhea (17%), and irritable bowel syndrome (5%).

Genital abnormalities

• Males have been described to have small penis/scrotum, hypospadias and congenital penile torsion.
• Minor cosmetic differences in female genitalia (e.g., labial and clitoral anomalies) were reported in multiple individuals who have not had functional consequences.

Hearing impairment. While uncommon, some individuals have sensorineural hearing loss.

Additional features

• Congenital heart defects are seen in 2% of affected individuals, though there do not appear to be common cardiac findings.
• Congenital anomalies of the kidney and urinary tract include renal agenesis (1%), hydronephrosis (1%), and urinary reflux (2%) [Boyle et al 2021].

Prognosis. KIF1A-NDD is a progressive disorder. Individuals with KIF1A-NDD often live to adulthood; however, certain genotypes are consistently associated with shortened life span (see Genotype-Phenotype Correlations). Typical causes of death in KIF1A-NDD include seizures and respiratory failure in the setting of aspiration or an intercurrent infection.

Genotype-Phenotype Correlations

Kinesin-like protein KIF1A (KIF1A) is comprised of a motor domain (the first ~360 amino acids) and a tail domain (the remainder of the protein). Most disease-causing variants in both simple KIF1A-associated neurologic disorders (KAND) and KIF1A-NDD (also called complex KAND) occur in the motor domain, while pathogenic variants associated with hereditary sensory and autonomic neuropathy (HSAN KAND) and amyotrophic lateral sclerosis (ALS KAND) are more often in the tail domain [Boyle et al 2021, Ghafoor et al 2024, Zhao et al 2024] (see also Genetically Related Disorders).

Within the motor domain, certain highly conserved functional regions are involved in ATP and microtubule binding: the P loop (97-103), switch I (202-217), and switch II (248-325). Pathogenic variants in these regions of the motor domain are commonly seen in KIF1A-NDD and are often associated with increased disease severity [Boyle et al 2021].

Phenotypes associated with recurrent variants associated with severe phenotypes. One of the pathogenic variants associated with the most severe phenotype is c.757G>A (p.Glu253Lys); many affected individuals with this variant die in their first few years of life. The oldest known individual with this variant is not yet age 10 years at the time of writing [Nemani et al 2020, Boyle et al 2021].

Another variant consistently associated with a severe phenotype is c.296C>T (p.Thr99Met). This variant is also associated with reduced life span, though one individual with this variant is in their early 20s [Boyle et al 2021, Nicita et al 2021].

Individuals with either of the above two variants are largely non-verbal, non-ambulatory, and frequently have such profound hypotonia that they require gastrostomy tube placement.

Recurrent variants associated with milder phenotypes. Even though most pathogenic variants associated with KIF1A-NDD are de novo, the large number of recurrent variants has allowed for additional genotype-phenotype analysis. Morison et al [2026] examined the clinical findings associated with five common recurrent variants: c.32G>A (p.Arg11Gln), c.647G>A (p.Arg216His), c.760C>T (p.Arg254Trp), c.920G>A (p.Arg307Gln), and c.946C>T (p.Arg316Trp). Individuals with the p.Arg11Gln variant or the p.Arg216His variant had milder phenotypes, with many individuals able to combine spoken words at age 2-3 years. In contrast, individuals with the p.Arg254Trp variant reached the same milestone at age 4-5 years, while individuals with the p.Arg307Gln were largely unable to combine words. The p.Arg316Trp variant had a much more variable phenotype.

Nomenclature

KIF1A-NDD has also been referred to as progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and KIF1A-related Rett syndrome [Langlois et al 2016, Wang et al 2019].

Prevalence

About 300 individuals with KIF1A-NDD have been reported worldwide (see Clinical Description).

Simple KAND

Age of onset tends to be later than in KIF1A-NDD, with some individuals developing manifestations in late childhood or adolescence; many remain asymptomatic until adulthood.

Neurologic problems

• Hypertonia and spasticity are seen in most individuals, often in lower extremities more than upper extremities. (Some individuals have an uncomplicated (pure) hereditary spastic paraplegia.)
• Urinary urgency and urinary incontinence
• Peripheral neuropathy, specifically in lower extremities
• Weakness and muscle atrophy, especially in the lower extremities

Motor impairment

• Progressive gait disturbance is a common presenting manifestation. Many individuals require adaptive equipment to remain ambulatory.
• Dystonic movements
• Hyperkinetic movement disorder (e.g., stereotypic movements, tics, dystonia)
• Ataxia

Brain MRI findings. Most individuals have normal MRI findings.

Prognosis. Based on current data, life span does not appear to be limited for individuals with simple KAND.

Molecular genetics. Associated pathogenic variants have been reported both inside and outside the KIF1A motor domain.

HSAN KAND

HSAN KAND has a distinctive clinical phenotype. Affected individuals typically present with distal sensory loss that progresses to ulceration and, frequently, amputation of digits.

Molecular genetics. HSAN KAND is associated with biallelic KIF1A pathogenic variants, including at least one frameshift variant in the alternatively spliced exon 25b [Ghafoor et al 2024].

See Hereditary Sensory and Autonomic Neuropathy Type II.

ALS KAND

Consistent with other types of amyotrophic lateral sclerosis (ALS), ALS KAND is a neurodegenerative disorder involving both upper and lower motor neurons with typical age at onset between 40 and 60 years. Some early studies suggested ALS KAND may be associated with an increased prevalence of sensory disturbances, but this has not borne out with subsequent publications [Liao et al 2022, Olsen et al 2024, Zheng et al 2024].

Prognosis. Roughly half of individuals die within five years of symptom onset [Liao et al 2022, Bernard et al 2024, Olsen et al 2024, Zhao et al 2024, Zheng et al 2024].

Molecular genetics. In all but two reported individuals, ALS KAND has been caused by missense variants or small indels outside the motor domain [Liao et al 2022, Bernard et al 2024, Olsen et al 2024, Zhao et al 2024, Zheng et al 2024]. Two individuals with ALS KAND and pathogenic variants in the motor domain of KIF1A had relatively early onset in their mid-30s, and both were still living at the time of publication [Bernard et al 2024, Olsen et al 2024].

See Amyotrophic Lateral Sclerosis Overview.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with KIF1A-NDD, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for KIF1A-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A small number of individuals with dominant-negative disease-causing variants in KIF1A are participating in an ongoing study of an allele-selective antisense oligonucleotide therapy to reduce expression of the pathogenic allele [Ziegler et al 2024]. Initial evaluations of the first recipient showed some improvement in seizures and gross motor skills, suggesting these therapies show some promise in altering the clinical outcome for affected individuals.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

KIF1A-related neurodevelopmental disorder (KIF1A-NDD) can be inherited in an autosomal dominant or, less commonly, autosomal recessive manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with autosomal dominant KIF1A-NDD have the disorder as the result of a de novo KIF1A pathogenic variant.
• Some individuals diagnosed with autosomal dominant KIF1A-NDD have an affected parent.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of a KIF1A pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the KIF1A pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [Paprocka et al 2023].* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a KIF1A pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Pathogenic variants in KIF1A appear to have near complete penetrance. While some intrafamilial variability has been reported, affected sibs with the same pathogenic KIF1A variant would be expected to show largely similar manifestations.
• If the KIF1A pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the KIF1A pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for KIF1A-NDD because of the possibility of parental gonadal mosaicism.

Offspring of a proband

• Individuals with KIF1A-NDD rarely reproduce.
• Each child of an individual with KIF1A-NDD has a 50% chance of inheriting the KIF1A pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the KIF1A pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive KIF1A-NDD are presumed to be heterozygous for a KIF1A pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a KIF1A pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygous parents of a child with autosomal recessive KIF1A-NDD are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a KIF1A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygous sibs of a child with autosomal recessive KIF1A-NDD are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Individuals with KIF1A-NDD rarely reproduce.
• The offspring of an individual with autosomal recessive KIF1A-NDD are obligate heterozygotes (carriers) for a pathogenic variant in KIF1A.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a KIF1A pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the KIF1A pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the KIF1A pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

KIF1A encodes kinesin-like protein KIF1A (KIF1A) is an ATP-dependent molecular motor protein that transports a variety of cargo along axonal microtubules [Chiba et al 2023]. KIF1A functions as a dimer when acting as a transporter; however, it is thought to be monomeric in solution. Most individuals with KIF1A-NDD have missense variants in the motor domain. Heterodimers of functional and disease-associated KIF1A proteins have reduced motility, suggesting many of these variants reduce transport by acting in a dominant-negative fashion. Depending on the specific residue involved, mutated proteins have been shown to have reduced binding to microtubules, reduced run length or velocity, or increased binding to microtubules resulting in a rigor state. Studies have shown a correlation between molecular mechanism of protein dysfunction and disease severity [Boyle et al 2021, Chiba et al 2023].

Mechanism of disease causation. Largely dominant-negative; however, mild phenotypes are associated with haploinsufficiency.

Author Notes

Contact Dr Lia Boyle (ude.hcimu.dem@obail) or Dr Wendy Chung (ude.dravrah.snerdlihc@gnuhc.ydnew) to inquire about review of KIF1A variants of uncertain significance.

Revision History

• 2 April 2026 (bp) Review posted live
• 1 December 2025 (wc) Original submission

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