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Biomedical subjects

Fuki M Hisama

Publications and source records attributed to Fuki M Hisama.

9 recordsLinked to original sources
PubMed2025

Imprecision medicine: Systematic gaps in reporting variants of uncertain significance (VUS) and their reclassifications.

PURPOSE: Variants of uncertain significance (VUS) are frequently encountered during clinical genetic testing. To explore the clinical burden of VUS, we developed the Brotman Baty Institute Clinical Variant Database, which is an electronic health record (EHR)-linked database of clinical germline genetic variant information from patients with rare genetic disorders seen at 2 tertiary academic medical centers. METHODS: We retrospectively reviewed EHRs and genetic testing reports from 5158 patients seen across diverse adult genetics practices at these institutions from 2015 to 2024. We also compared these EHR-based variant classifications with those in ClinVar. RESULTS: The number of reported VUS relative to pathogenic or likely pathogenic variants can vary by over 14-fold depending on the primary indication for genetic testing and 3-fold depending on self-reported race. Furthermore, at least 1.6% of variant classifications used in the EHR for clinical care are outdated based on ClinVar variant classifications, including 26 instances in which the testing lab updated ClinVar, but the reclassification was never communicated to the patient. CONCLUSION: Our findings reveal that the clinical burden of VUS in adult medical genetics is unequally distributed across patients. We also highlight a deficiency in existing systems for communicating variant reclassifications to ClinVar, patients, and providers.

Humans↗
PubMed2006

Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia.

Myokymia is characterized by spontaneous, involuntary muscle fiber group contraction visible as vermiform movement of the overlying skin. Myokymia with episodic ataxia is a rare, autosomal dominant trait caused by mutations in KCNA1, encoding a voltage-gated potassium channel. In the present study, we report a family with four members affected with myokymia. Additional clinical features included motor delay initially diagnosed as cerebral palsy, worsening with febrile illness, persistent extensor plantar reflex, and absence of epilepsy or episodic ataxia. Mutation analysis revealed a novel c.676C>A substitution in the potassium channel gene KCNA1, resulting in a T226K nonconservative missense mutation in the Kv1.1 subunit in all affected individuals. Electrophysiological studies of the mutant channel expressed in Xenopus oocytes indicated a loss of function. Co-expression of WT and mutant cRNAs significantly reduced whole-oocyte current compared to expression of WT Kv1.1 alone.

Amino Acid Sequence↗
PubMed2006

Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons.

Inherited erythromelalgia/erythermalgia (IEM) is a neuropathy characterized by pain and redness of the extremities that is triggered by warmth. IEM has been associated with missense mutations of the voltage-gated sodium channel Na(V)1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Na(V)1.7, with only two mutations in segment 4 (S4) and S6 of domain I. We report here a simplex case with an alanine 863 substitution by proline (A863P) in S5 of domain II of Na(V)1.7. The functional effect of A863P was investigated by voltage-clamp analysis in human embryonic kidney 293 cells and by current-clamp analysis to determine the effects of A863P on firing properties of small DRG neurons. Activation of mutant channels was shifted by -8 mV, whereas steady-state fast inactivation was shifted by +10 mV, compared with wild-type (WT) channels. There was a marked decrease in the rate of deactivation of mutant channels, and currents elicited by slow ramp depolarizations were 12 times larger than for WT. These results suggested that A863P could render DRG neurons hyperexcitable. We tested this hypothesis by studying properties of rat DRG neurons transfected with either A863P or WT channels. A863P depolarized resting potential of DRG neurons by +6 mV compared with WT channels, reduced the threshold for triggering single action potentials to 63% of that for WT channels, and increased firing frequency of neurons when stimulated with suprathreshold stimuli. Thus, A863P mutant channels produce hyperexcitability in DRG neurons, which contributes to the pathophysiology of IEM.

Action Potentials↗
PubMed2006

WRN's tenth anniversary.

Werner syndrome (WS) is a segmental progeroid syndrome in which patients display pleiotropic features of aging seen in the normal population. The advent of positional cloning in the 1990s markedly accelerated the identification of human disease-causing genes. In 1996, mutations in WRN, which was shown to encode a new, putative member of the family of RecQ DNA helicases, were identified in four patients as the cause of WS. Ten years after the identification of WRN, what have we learned about its role in WS, and its contribution to normal aging?

Adult↗
PubMed2005

Rapid array-based genomic characterization of a subtle structural abnormality: a patient with psychosis and der(18)t(5;18)(p14.1;p11.23).

Array-based copy number analysis has recently emerged as a rapid means of mapping complex and/or subtle chromosomal abnormalities. We have compared two such techniques, using bacterial artificial chromosome (BAC) and single nucleotide polymorphism (SNP) arrays in the evaluation of a 45-year-old woman with dysmorphic features, mental retardation, psychosis, and an unbalanced derivative chromosome 18, (46,XX, der(18)t(18;?)(p12;?)). Both array-based methods demonstrated that the additional material on chromosome 18 was of 5p origin. The 5p duplication mapped telomeric to 25.320 Mb (BAC array) and 25.607 Mb (SNP array), corresponding to the band 5p14.1. Both BAC and SNP arrays also showed a deletion involving chromosome 18p extending telomeric from 8.437 Mb (BAC array) and 8.352 Mb (SNP array), corresponding to the band 18p11.23. Molecular cytogenetic mapping using fluorescence in situ hybridization (FISH) supported the array findings and further refined the breakpoint regions, confirming that the BAC and SNP chips were both useful in this regard. Both case reports and linkage analyses have implicated these chromosomal intervals in psychosis. The array-based experiments were completed over the course of several days. While these methods do not eliminate the requirement for traditional fine-mapping, they provide an efficient approach to identifying the origin and extent of deleted and duplicated material in chromosomal rearrangements.

Chromosome Banding↗
PubMed2005

Familial periodic paralysis and Charcot-Marie-Tooth disease in a 7-generation family.

BACKGROUND: A family with a complicated constellation of neurologic findings, including neuropathy, myotonia, and periodic paralysis, has been described in 4 studies in the medical literature since 1934. The underlying cause of their disease has been the subject of considerable speculation and has never been identified until now. OBJECTIVE: To identify the molecular basis of this family's neurologic disease. DESIGN: The coding regions of 6 genes that cause peripheral neuropathy and regions of the muscle sodium channel gene (SCN4A) were sequenced. RESULTS: A novel missense mutation (Arg67Pro) in the myelin protein zero gene was identified in 2 patients with Charcot-Marie-Tooth disease, and a common missense mutation (Thr704Met) was identified in the SCN4A gene in 4 family members. We discuss the difficulties of genotype-phenotype correlation in this family. CONCLUSIONS: These findings indicate that 2 independent mutations segregating in this family are responsible for the puzzling clinical picture.

Adolescent↗
PubMed2003

Novel LGI1 mutation in a family with autosomal dominant partial epilepsy with auditory features.

Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare idiopathic epilepsy syndrome caused by mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene. The authors report that molecular genetic studies in seven affected family members identified a novel F318C substitution that alters a highly conserved residue in a predicted repeat domain of unknown function. This report suggests that this domain may participate in the development of the ADPEAF phenotype.

Aged↗