Alternative titles; symbols
HGNC Approved Gene Symbol: KIF5A
SNOMEDCT: 732948003;
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38): 12:57,550,044-57,586,633 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.3 | {Amyotrophic lateral sclerosis, susceptibility to, 25} | 617921 | Autosomal dominant | 3 |
| Myoclonus, intractable, neonatal | 617235 | Autosomal dominant | 3 | |
| Spastic paraplegia 10, autosomal dominant | 604187 | Autosomal dominant | 3 |
Kinesins are microtubule-based motor proteins involved in the transport of organelles in eukaryotic cells. They typically consist of 2 identical, approximately 110- to 120-kD heavy chains, such as KIF5A, and 2 identical, approximately 60- to 70-kD light chains. The heavy chain contains 3 domains: an N-terminal globular domain, a long alpha-helical coiled coil domain, and a small C-terminal globular domain. Unlike KIF5B (602809), which is ubiquitously expressed, KIF5A is expressed exclusively in neurons (summary by Niclas et al., 1994).
By screening a human hippocampal cDNA library with a fragment of a human kinesin heavy chain (KHC) expressed sequence tag clone, Niclas et al. (1994) isolated cDNAs encoding NKHC. The predicted 1,032-amino acid protein has the characteristic features of a KHC, as well as a unique C-terminal stretch of 69 amino acids. The amino acid sequence of NKHC is 65% and 54% identical to the amino acid sequences of KNS1 and the Drosophila KHC, respectively. Northern blot analysis of rat tissues detected Nkhc expression only in brain, where multiple transcripts were found. Immunoblot analysis of rat tissue extracts using antibodies specific for NKHC detected a doublet of approximately 120 and 133 kD only in brain and sciatic nerve tissue. By indirect immunofluorescence, the authors showed that NKHC is distributed throughout the central nervous system but is highly enriched in subsets of neurons. Within cultured hippocampal neurons, NKHC is concentrated in the cell body, particularly in the perinuclear region.
Lawrence et al. (2004) presented a standardized kinesin nomenclature based on 14 family designations. Under this system, KIF5A belongs to the kinesin-1 family.
By FISH, Hamlin et al. (1998) mapped the KIF5A and GALGT (601873) genes to 12q13. They found that these genes are contained within the same approximately 200-kb YAC insert as the GLI (165220) and DDIT3 (126337) genes.
Kinesins have N-terminal motor domains and C-terminal cargo-binding tail domains separated by hinge regions. Kanai et al. (2004) found that the hinge and C-terminal tail regions of Kif5a, Kif5b, and Kif5c (604593) bound a large detergent-resistant RNase-sensitive granule from mouse brain. Mass spectrometric analysis showed that the granule contained mRNAs for Camk2-alpha (CAMK2A; 114078) and Arc (NOL3; 605235) and 42 proteins, including those for RNA transport, protein synthesis, and translational silencing. The granule localized to dendrites and underwent bidirectional movement. Distally directed movement of the granule was enhanced by Kif5 overexpression and reduced by Kif5 functional blockage. Kanai et al. (2004) concluded that kinesins transport RNA in dendrites via this large granule.
Spastic Paraplegia 10
In affected members of the original family with hereditary spastic paraplegia found to be linked to chromosome 12q13 (SPG10; 604187), Reid et al. (2002) identified a missense mutation in the KIF5A gene (602821.0001). The mutation occurred at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding. Mutation of kinesin orthologs in various species leads to phenotypes resembling hereditary spastic paraplegia. The kinesin motor powers intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. The findings in this family suggested that the underlying pathology of SPG10 and possibly of other forms of hereditary spastic paraplegia may involve perturbations of neuronal anterograde (or retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest axons of the central nervous system.
To define the phenotype and frequency of SPG10 better, Goizet et al. (2009) sequenced the KIF5A gene in 175 probands with autosomal dominant hereditary spastic paraplegia and 30 patients with sporadic disease in whom mutations in several other SPG-related genes were excluded. Most of the patients were French. Eight different heterozygous pathogenic mutations (see, e.g., 602821.0002; 602821.0005-602821.0007) were found in 8 (4.8%) of 175 families, with a frequency among French families of 5.1% (8 of 156 French families). All of the mutations were located in the highly conserved motor domain. The clinical features of 17 patients from these families were reviewed in detail. Although the age at onset varied, most had onset during the third or fourth decade, and all presented with gait abnormalities resulting from stiffness in the lower extremities. All patients had lower limb hyperreflexia, spasticity, and extensor plantar responses, usually associated with lower limb weakness. Upper limb spasticity and bladder dysfunction were frequent, but not always observed. Sensory disturbances were common: 10 patients (59%) had decreased vibration sense and 9 (53%) had distal hypoesthesia. Disease progression was mild to moderate, and all patients were still able to walk without help even many years after onset. Affected individuals in 7 of the 8 families had a complicated form of SPG with variable additional features, including axonal sensorimotor peripheral neuropathy, severe amyotrophy of the hands, mild to moderate mental retardation, and parkinsonism. One patient had deafness and another had retinitis pigmentosa. There was intrafamilial variability: in 1 family, the proband had a pure form of SPG, whereas his father had only axonal neuropathy and no spasticity.
Crimella et al. (2012) identified heterozygous mutations (see, e.g., 602821.0006; 602821.0008-602821.0009) in 4 (8.8%) of 45 Italian probands with autosomal dominant spastic paraplegia. A heterozygous mutation was also found in 1 (1%) of 94 patients with sporadic SPG. In 2 families, the disorder was accompanied by axonal sensorimotor peripheral neuropathy. In 1 (2.7%) of 36 patients with CMT tested for mutations in the KIF5A gene, Crimella et al. (2012) identified a de novo heterozygous mutation in the motor domain (G235E; 602821.0009). The findings suggested that axonal neuropathy may represent an extreme end of the spectrum of neurologic disorders associated with KIF5A mutations.
Neonatal Intractable Myoclonus
In 2 unrelated patients with neonatal intractable myoclonus (NEIMY; 617235), Duis et al. (2016) reported different de novo heterozygous frameshift mutations in the KIF5A gene (c.2854delC, 602821.0011 and c.2934delG, 602821.0012), both of which were predicted to result in a stop-loss with read-through of the normal termination codon to create an elongated protein with 14 additional residues. The predicted abnormal protein was the same in both cases. The c.2854delC mutation was found in case 1 by whole-exome sequencing. The c.2934delG mutation was initially found in case 2 by DaRe et al. (2013) by sequencing of a panel of genes involved in mitochondrial function. Both mutations were confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutations were predicted to result in a dominant-negative effect on the kinesin complex, thus disrupting organelle transport in neurons. The clinical features were consistent with mitochondrial dysfunction within neurons, likely resulting from abnormal mitochondrial transport due to an abnormal kinesin 'motor.' Duis et al. (2016) noted that the C-terminal region of KIF5A binds GABARAP (605125), which clusters neurotransmitter receptors by mediating interaction with microtubules. These data suggested that the myoclonus in these patients may be caused by increased neuronal excitation due to aberrant GABA signaling.
In a male infant with NEIMY, Rydzanicz et al. (2016) identified a de novo heterozygous stop-loss mutation in the KIF5A gene (602821.0013). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. Rydzanicz et al. (2016) speculated that the mutation induced abnormal binding to TRAK2 (607334) or other kinesin adaptor proteins.
Susceptibility to Amyotrophic Lateral Sclerosis 25
In 12 patients from 9 unrelated families with amyotrophic lateral sclerosis-25 (ALS25; 617921), Nicolas et al. (2018) identified heterozygous loss-of-function (LOF) variants in the C-terminal region of the KIF5A gene (see, e.g., 602821.0014-602821.0016). The KIF5A gene was chosen as a candidate gene for study based on the results of a genomewide association study (GWAS) of several cohorts encompassing 20,806 ALS cases and 59,804 controls. In the GWAS, there was a significant association between a P986L missense variant (rs113247976) in the KIF5A gene and ALS (OR = 1.38, p = 6.4 x 10(-10)). The ALS association with P986L was replicated in 4,159 additional ALS cases and 18,650 controls. The authors noted that this missense variant may not be the primary risk factor and may be in linkage disequilibrium with other causative variants, or that it may be a common, low-penetrance risk allele. The LOF point mutations were initially found among a cohort of 1,138 probands with familial ALS and 19,494 controls who underwent exomewide rare variant burden (RVB) analysis for association of LOF variants. Nicolas et al. (2018) identified 6 heterozygous LOF variants in the KIF5A gene in patients (0.53%) compared to 3 such variants among the controls (0.015%). Further analysis of this patient cohort identified 2 small indels in the KIF5A gene (Asp996fs and Asn999fd) that were predicted to result in a frameshift. Variation in the KIF5A gene reached exomewide significance (OR = 41.16, p = 3.8 x 10(-9)). Two of the variants (602821.0014 and 602821.0015) were confirmed by Sanger sequencing and segregated with the disorder in the 2 unrelated families. All ALS-associated KIF5A variants occurred within a 34-bp stretch of DNA and were predicted to affected splicing of exon 27, which encodes amino acids 998-1007. The mutations were predicted to result in the complete skipping of exon 27, yielding a transcript with a frameshift at residue 998, the deletion of the normal C-terminal 34 amino acids of the cargo-binding domain, and the extension of an aberrant 39 amino acids to the C terminus. The 2 small indels were predicted to have a similar effect near exon 27. Mutational screening of KIF5A in an additional cohort of 9,046 ALS cases, mainly sporadic patients, identified 3 additional carriers of C-terminal variants. Splicing abnormalities were confirmed in cells derived from 2 unrelated patients with mutations. Nicolas et al. (2018) noted that KIF5A mutations associated with SPG10 are almost exclusively missense mutations that affect the N-terminal motor domain, whereas mutations associated with ALS are found predominantly in the C-terminal cargo-binding region, suggesting a genotype/phenotype correlation. Nicolas et al. (2018) speculated that KIF5A variants cause disease by disrupting axonal transport. The variants identified, in the cargo-binding domain, may cause accumulation of cytoplasmic proteins aggregates at the neuronal cell body, resulting in a deficiency of certain cargo proteins at neurite terminals.
In 3 unrelated probands with familial ALS25, Brenner et al. (2018) identified 3 different mutations in the KIF5A gene (see, e.g., 602821.0017). The mutations, which were found by whole-exome sequencing of a cohort of 426 probands, were confirmed by Sanger sequencing. In each case, family segregation studies suggested that the mutation segregated with the disorder, but DNA was not available from other affected family members to confirm. There was also evidence of incomplete penetrance. All 3 mutations (c.2993-1G-A, c.3019A-G, and 3020+2T-C) occurred in the C terminus in or near exons 26 and 27, and all were predicted to result in splicing abnormalities. Aberrant splicing was confirmed in lymphoblasts from 1 of the patients. The variants identified were similar to a c.3020+1G-A variant reported in the ALS Variant Server database. Brenner et al. (2018) postulated haploinsufficiency as the pathogenic mechanism. In addition, Brenner et al. (2018) found the P986L variant in the KIF5A gene in 29 of the 426 patients with familial ALS (allele frequency of 3.4%) compared to 123 of 6,137 controls (allele frequency of 1%) and the gnomAD database (allele frequency of 1.13%). However, 11 of the 29 patients carrying this missense variant also had heterozygous variants in other ALS-associated genes. Analysis of lymphoblasts carrying the P986L variant showed that the variant did not have any effect on splicing, and mRNA levels were similar to those of controls.
Pant et al. (2022) studied the phenotype of HEK293 cells that were transfected with a mutant KIF5A gene with skipping of exon 27 (ex27del) and an aberrant 39-amino acid C terminus (see 602821.0017). The KIF5A ex27del protein, which interacted with and sequestered wildtype KIF5A, formed abnormal cytoplasmic granules. Transfection of the ex27del mutation into primary mouse cortical neurons resulted in compromised autoinhibition and enhanced processivity of microtubules, suggesting a gain-of-function mechanism. Pant et al. (2022) then studied the cellular phenotypes of motor neurons derived from iPSCs that were generated from peripheral blood mononuclear cells from 3 patients with ALS25. One patient had a heterozygous c.3020+2T-C transition in intron 26 of KIF5A and the other 2 patients had a heterozygous c.2993-1A-G transition in intron 26 of KIF5A. Both mutations were shown to result in expression of an aberrant 39-amino acid C-terminal sequence. The induced motor neurons showed abnormal KIF5A inclusions.
Pant et al. (2022) generated a Drosophila model that constitutively expressed a mutant KIF5A gene with skipping of exon 27 (ex27del) and an aberrant 39-amino acid C terminus (see 602821.0017) that had been identified in a patient with ALS25. The mutant flies had unexpanded wings and early lethality. When the KIF5A ex27del mutation was confined to only muscles, the mutant flies had a reduced life span. When the KIF5A ex27del mutation was expressed in only motor neurons, the flies had impaired climbing.
In the original family identified as suffering from autosomal dominant hereditary spastic paraplegia-10 (604187), Reid et al. (2002) identified an asn256-to-ser (N256S) mutation in the KIF5A gene.
Ebbing et al. (2008) stated that N256S resides in KIF5A loop 11, a region that connects microtubule- and ATP-binding sites. The N256S substitution reduced microtubule-dependent ATPase activity in vitro, but its affinity for microtubules was only slightly decreased over wildtype. When mixed in a 50:50 ratio with wildtype KIF5A, the N256S mutant behaved in a dominant-negative fashion in several in vitro motor gliding and cargo transport assays.
In affected members of a 4-generation family with spastic paraplegia-10 (SPG10; 604187), Fichera et al. (2004) identified a heterozygous 838C-T transition in the KIF5A gene, resulting in an arg280-to-cys (R280C) substitution in a region of the protein involved in microtubule binding activity and included in the switch II cluster within the motor domain. The arg280 residue is highly conserved, and the authors predicted that the R280C mutation resulted in a loss of protein function.
Goizet et al. (2009) identified a heterozygous R280C mutation in a French father and son with SPG10. In addition to spasticity, the phenotype was complicated by mild mental retardation and hand tremor in the son and axonal sensorimotor peripheral neuropathy in the father. Both also had pes cavus, urinary symptoms, and distal sensory impairment. The same codon was found to be mutated in another French family with the disorder (see R280H, 602821.0007), suggesting a mutation hotspot.
Liu et al. (2014) identified a heterozygous R280C mutation in a 39-year-old man who presented at age 8 years with peripheral neuropathy and later developed spasticity and cognitive dysfunction. An R280C mutation was also found in an unrelated 32-year-old woman who presented with spastic paraplegia at age 28 and later developed peripheral neuropathy and cognitive dysfunction. Functional studies of the variant were not performed.
In affected members of a large kindred with spastic paraplegia-10 (SPG10; 604187), Blair et al. (2006) identified a heterozygous 1035A-G transition in exon 10 of the KIF5A gene, resulting in a tyr276-to-cys (Y276C) substitution within the highly conserved kinesin motor domain of the protein. The mutation was not present in any unaffected family members or in 200 control chromosomes. Notably, all affected members had adult onset of symptoms (average age 36 years).
In an Italian patient with spastic paraplegia-10 (SPG10; 604187), Lo Giudice et al. (2006) identified a heterozygous 1082C-T transition in exon 11 of the KIF5A gene, resulting in an ala361-to-val (A361V) substitution in a highly conserved residue within the coiled-coil domain of the protein. The patient developed symptoms at age 35 years and reportedly had several affected family members spanning 4 generations. The mutation was not identified in 750 control chromosomes.
In a French woman with onset of pure spastic paraplegia-10 (SPG10; 604187) in her thirties, Goizet et al. (2009) identified a heterozygous 751G-A transition in exon 9 of the KIF5A gene, resulting in a glu251-to-lys (E251K) substitution in the motor domain. Her father, who also carried the mutation, had onset of axonal sensorimotor neuropathy in his fifties. He had lower limb amyotrophy and distal hypoesthesia, but no spasticity or hyperreflexia. The findings reflected marked intrafamilial variability of the phenotype and indicated that KIF5A mutations can be associated with a peripheral neuropathy.
In 4 affected members of a French family with spastic paraplegia-10 (SPG10; 604187), Goizet et al. (2009) identified a heterozygous 611G-A transition in exon 8 of the KIF5A gene, resulting in an arg204-to-gln (R204Q) substitution at a highly conserved residue in the switch I region of the motor domain. The phenotype was complicated, and included severe upper limb amyotrophy in 2 patients and distal sensory impairment in 3 patients, in addition to spasticity.
Crimella et al. (2012) identified a heterozygous R204Q mutation in an Italian parent and child with SPG10. An unrelated Italian patient with sporadic occurrence of the disorder was found to carry the same mutation. The patients had onset between ages 13 and 33 years of lower limb spasticity and weakness associated with hyperreflexia and extensor plantar responses. All also had pes cavus and an axonal sensorimotor polyneuropathy. Two patients had upper limb spasticity; 1 had mild cognitive impairment. The mutation was not found in 500 controls.
Liu et al. (2014) identified a heterozygous R204Q mutation in a 38-year-old man with onset of spastic paraplegia before age 20. He also developed peripheral axonal neuropathy and distal sensory impairment. Functional studies of the variant were not performed.
In a French mother and son with spastic paraplegia-10 (SPG10; 604187), Goizet et al. (2009) identified a heterozygous 839G-A transition in the KIF5A gene, resulting in an arg280-to-his (R280H) substitution at a highly conserved residue in the motor domain. Both patients had onset of spasticity in the first decade; the phenotype in the son was complicated by retinitis pigmentosa. The same codon was found to be mutated in another French family (see R280C, 602821.0002), suggesting a mutation hotspot.
Liu et al. (2014) identified a heterozygous R280H mutation in a 62-year-old woman who presented with axonal peripheral neuropathy at age 42 years. She had difficulty walking and mild distal sensory impairment, but no symptoms of spasticity. Functional studies of the variant were not performed.
In a 6.5-year-old Italian child with very early onset of spastic paraplegia-10 (SPG10; 604187), Crimella et al. (2012) identified a heterozygous 2263G-A transition in exon 20 of the KIF5A gene, resulting in a glu755-to-lys (E755K) substitution at a highly conserved residue in the stalk domain. This patient had onset at 1.2 years of lower limb spasticity, weakness, amyotrophy, hyperreflexia, and extensor plantar responses. There was also mild hyperreflexia and weakness of the upper limbs. The patient's father, who also carried the mutation, had only increased reflexes on examination at age 50 years. The mutation was not found in 500 controls.
In an Italian patient with a variant of spastic paraplegia-10 (SPG10; 604187) manifest only as axonal peripheral neuropathy, Crimella et al. (2012) identified a heterozygous de novo 704G-A transition in exon 8 of the KIF5A gene, resulting in a gly235-to-glu (G235E) substitution at a highly conserved residue in the switch II motif of the motor domain. The mutation was not found in 500 controls. The patient had onset of distal lower limb weakness and fatigability at age 16 years. At age 25, he had lower limb atrophy, pes cavus, scoliosis, ankle weakness, and clumsy gait. Physical examination showed distal atrophy of the lower limbs, mild weakness in the small hand muscles, decreased distal vibration and position senses, and areflexia of the lower limbs. There were no signs of spasticity. Electrophysiologic studies were consistent with an axonal sensorimotor neuropathy. The patient was 1 of 36 patients (2.7%) with Charcot-Marie-Tooth disease tested for mutations in the KIF5A gene. The findings suggested that isolated axonal peripheral neuropathy may represent an extreme end of the spectrum of neurologic disorders associated with KIF5A mutations.
In 2 brothers with variable manifestations of spastic paraplegia-10 (SPG10; 604187), Liu et al. (2014) identified a heterozygous c.694G-A transition in exon 8 of the KIF5A gene, resulting in an asp232-to-asn (D232N) substitution at a highly conserved residue in the switch II region of the motor domain. The mutation was not found in the Exome Variant Server database or in 221 control exomes. One brother presented with axonal peripheral neuropathy at age 40 years and later developed spasticity, whereas his brother had pure spastic paraplegia. Functional studies of the variant were not performed.
In a male infant with neonatal intractable myoclonus (NEIMY; 617235), Duis et al. (2016) identified a de novo heterozygous 1-bp deletion (c.2854delC) in the KIF5A gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was predicted to result in a stop-loss with read-through of the normal termination codon to create an elongated protein with 14 additional residues. The mutation was also predicted to result in a dominant-negative effect on the kinesin complex. Functional studies of the variant and studies of patient cells were not performed.
Duis et al. (2016) reported a female infant with neonatal intractable myoclonus (NEIMY; 617235) who had a de novo heterozygous 1-bp deletion (c.2934delC) in the KIF5A gene. The mutation, which was previously found in this patient by next-generation sequencing of a panel of genes involved in mitochondrial function by DaRe et al. (2013), was confirmed by Sanger sequencing. The mutation was predicted to result in a stop-loss with read-through of the normal termination codon to create an elongated protein with 14 additional residues. The mutation was also predicted to result in a dominant-negative effect on the kinesin complex. Functional studies of the variant and studies of patient cells were not performed.
In a Polish infant with neonatal intractable myoclonus (NEIMY; 617235), Rydzanicz et al. (2016) identified a de novo heterozygous 1-bp deletion (c.2921delC, NM_004984.2) in exon 26 of the KIF5A gene, predicted to result in a frameshift (Ser974fs) in the C-terminal cargo binding tail. The mutation was predicted to cause premature termination of the protein after introducing 14 residues. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC, Exome Sequencing Project, or 1000 Genomes Project databases, or in 1,343 Polish controls. Functional studies of the variant and studies of patient cells were not performed. Rydzanicz et al. (2016) speculated that the mutation induced abnormal binding to TRAK2 (607334) or other kinesin adaptor proteins.
In 3 sibs with amyotrophic lateral sclerosis-25 (ALS25; 617921), Nicolas et al. (2018) identified a heterozygous C-to-T transition (c.2993-3C-T, NM_004984.2) at the 5-prime splice junction of exon 27 of the KIF5A gene. The mutation was found by exomewide rare variant burden (RVB) analysis and confirmed by Sanger sequencing. Another brother was affected, but DNA was not available. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in the skipping of exon 27, the deletion of key residues in the cargo-binding domain, and the extension of aberrant residues to the C terminus.
In 2 sibs with amyotrophic lateral sclerosis-25 (ALS25; 617921), Nicolas et al. (2018) identified a heterozygous T-to-A transversion (c.3020+2T-A, NM_004984.2) at the 3-prime splice junction of exon 27 of the KIF5A gene. The mutation was found by exomewide rare variant burden (RVB) analysis and confirmed by Sanger sequencing. The sibs' mother was also affected, but DNA was not available. The mutation was predicted to result in the skipping of exon 27, the deletion of key residues in the cargo-binding domain, and the extension of aberrant residues to the C terminus. Patient lymphoblasts showed the presence of abnormal KIF5A transcripts with the skipping of exon 27. This splice form was not found in 4 control cell lines.
In a patient with amyotrophic lateral sclerosis-25 (ALS25; 617921), Nicolas et al. (2018) identified a heterozygous G-to-A transition (c.3020+1G-A, NM_004984.2) at the 3-prime splice junction of exon 27 of the KIF5A gene. The mutation was found by exomewide rare variant burden (RVB) analysis and confirmed by Sanger sequencing. The patient had a family history of ALS, but DNA from other family members was not available. The mutation was predicted to result in the skipping of exon 27, the deletion of key residues in the cargo-binding domain, and the extension of aberrant residues to the C terminus. Patient peripheral blood mononuclear cells showed the presence of abnormal KIF5A transcripts with the skipping of exon 27. This splice form was not found in 4 control cell lines.
In a patient with amyotrophic lateral sclerosis-25 (ALS25; 617921), Brenner et al. (2018) identified a heterozygous c.3019A-G transition (c.3019A-G, NM_004984) in exon 27 of the KIF5A gene, predicted to result in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. RNA analysis of patient lymphocytes showed that the mutation disrupted the splice donor site of intron 27, resulting in the skipping of exon 27, which was predicted to cause a frameshift and premature termination (Asn999ValfsTer39).
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