Clinical Deep Phenotyping of ABCA7 Mutation Carriers

Background and ObjectivesPutative loss-of-function (pLOF) ABCA7 variants that increase Alzheimer disease (AD) risk were identified; however, deep phenotypic characterization of these variants in mutation carriers is limited. We aimed to obtain deep clinical phenotypes of ABCA7 pLOF mutation carriers from a large retrospectively reviewed series.MethodsGenotypes were determined for 5,353 individuals evaluated at Mayo Clinic for 6 reported ABCA7 pLOF variants (p.E709fs, p.Trp1214X, p.L1403fs, c.4416+2T>G, p.E1679X, and c.5570+5G>C). Medical records of 100 mutation carriers were reviewed for demographics, clinical phenotypes, and diagnoses. Eleven mutation carriers had autopsy-based neuropathologic diagnoses.ResultsWe confirmed that ABCA7 pLOF mutations confer AD risk in our series of 2,495 participants with AD and 2,858 cognitively unaffected participants. Clinical review of 100 mutation carriers demonstrated phenotypic variability of clinical presentations with both memory and nonmemory cognitive impairment and a subset presenting with motor symptoms. There was a wide range of age at onset of cognitive symptoms (ages 56–92 years, mean = 75.6). Ten of the 11 autopsied mutation carriers had AD neuropathology. ABCA7 pLOF mutation carriers had higher rates of depression (41.6%) and first-degree relatives with cognitive impairment (38.1%) compared with the general population.DiscussionOur study provides a deep clinical review of phenotypic characteristics of mutation carriers for 6 ABCA7 pLOF mutations. Although memory impairment was the most common initial symptom, nonmemory cognitive and/or motor symptoms were present in a substantial number of mutation carriers, highlighting the heterogeneity of clinical features associated with these mutations. Likewise, although AD neuropathology is the most common, it is not the only autopsy-based diagnosis. Presence of earlier ages at onset, higher rates of depression, and first-degree relatives with cognitive impairment among mutation carriers suggest that these genetic variants may have more aggressive clinical features than AD in the general population. This deep phenotyping study of ABCA7 pLOF mutation carriers provides essential genotype-phenotype correlations for future precision medicine approaches in the clinical setting.

Revealing the Mutational Spectrum in Southern Africans With Amyotrophic Lateral Sclerosis

Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.

TNNI1 Mutated in Autosomal Dominant Proximal Arthrogryposis

ObjectivesThe main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis.MethodsWe performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing.ResultsA 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in TNNI1 in the family.DiscussionThe altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with TNNI2 variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a TNNI1 nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of TNNI1 in the disease.

Homozygous SOD1 Variation L144S Produces a Severe Form of Amyotrophic Lateral Sclerosis in an Iranian Family

ObjectivesAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by degeneration of motor neurons determining progressive muscular atrophy, weakness, and death from respiratory failure.MethodsHere, we report clinical and molecular findings of a novel Iranian family affected with a severe form of early-onset familial ALS.ResultsThree siblings born to consanguineous parents developed a form of ALS characterized by early-onset lower limb involvement and a fast progression, proving fatal at age 16 years for 1 of them. Molecular analysis of the SOD1 gene revealed the homozygous substitution c.434T>C in exon 5 resulting in the amino acid change p.Leu144Ser (L144S), previously reported as a dominant variant. Both parents were heterozygous carriers. The probands' mother recently developed a late-onset ALS with predominant upper motor neuron involvement.DiscussionThis report adds p.L144S to the short list of homozygous SOD1 variants and suggests that the development of an earlier-onset and/or faster disease progression can occur when 2 mutated alleles are present.

Multigene Panel Testing in a Large Cohort of Adults With Epilepsy

Background and ObjectivesAlthough genetic testing among children with epilepsy has demonstrated clinical utility and become a part of routine testing, studies in adults are limited. This study reports the diagnostic yield of genetic testing in adults with epilepsy.MethodsUnrelated individuals aged 18 years and older who underwent diagnostic genetic testing for epilepsy using a comprehensive, next-generation sequencing-based, targeted gene panel (range 89–189 genes) were included in this cross-sectional study. Clinical information, provided at the discretion of the ordering clinician, was reviewed and analyzed. Diagnostic yield was calculated for all individuals including by age at seizure onset and comorbidities based on clinician-reported information. The proportion of individuals with clinically actionable genetic findings, including instances when a specific treatment would be indicated or contraindicated due to a diagnostic finding, was calculated.ResultsAmong 2,008 individuals, a diagnostic finding was returned for 218 adults (10.9%), with clinically actionable findings in 55.5% of diagnoses. The highest diagnostic yield was in adults with seizure onset during infancy (29.6%, 0–1 year), followed by in early childhood (13.6%, 2–4 years), late childhood (7.0%, 5–10 years), adolescence (2.4%, 11–17 years), and adulthood (3.7%, ≥18 years). Comorbid intellectual disability (ID) or developmental delay resulted in a high diagnostic yield (16.0%), most notably for females (19.6% in females vs 12.3% in males). Among individuals with pharmacoresistant epilepsy, 13.5% had a diagnostic finding, and of these, 57.4% were clinically actionable genetic findings.DiscussionThese data reinforce the utility of genetic testing for adults with epilepsy, particularly for those with childhood-onset seizures, ID, and pharmacoresistance. This is an important consideration due to longer survival and the complexity of the transition from pediatric to adult care. In addition, more than half of diagnostic findings in this study were considered clinically actionable, suggesting that genetic testing could have a direct impact on clinical management and outcomes.

Transcript-Specific Loss-of-Function Variants in VPS16 Are Enriched in Patients With Dystonia

Background and ObjectivesOur objective was to improve rare variant interpretation using statistical measures as well as publicly accessible annotation of expression levels and tissue specificity of different splice isoforms. We describe rare VPS16 variants observed in patients with dystonia and patients without dystonia, elaborate on our interpretation of VPS16 variants affecting different transcripts, and provide detailed clinical description of the movement disorder caused by VPS16 variants.MethodsIn-house exome and genome data sets (n = 11,539) were screened for rare heterozygous missense and putative loss-of-function (pLoF) variants in VPS16. Using pext (proportion expressed across transcripts) values from the Genome Aggregation Database (gnomAD), we differentiated variants affecting weakly and highly expressed exons/transcripts and applied statistical measures to systematically identify disease-associated genetic variation among patients with dystonia (n = 280).ResultsSix different heterozygous pLoFs in VPS16 transcripts were identified in 13 individuals. Three of these pLoFs occurred in 9 individuals with different phenotypes, and 3 pLoFs were identified in 4 unrelated individuals with early-onset dystonia. Although pLoFs were enriched in the dystonia cohort (n = 280; p = 2.04 × 10−4; 4/280 cases vs 9/11,259 controls; Fisher exact test), it was not exome-wide significant. According to the pext values in gnomAD, all 3 pLoFs observed in the patients with dystonia were located in the highly expressed canonical transcript ENST00000380445.3, whereas 2 of 3 pLoFs detected in 8 individuals without dystonia were located in the first exon of the noncanonical transcript ENST00000380443.3 that is weakly expressed across all tissues. Taking these biological implications into account, pLoFs involving the canonical transcript were exome-wide significantly enriched in patients with dystonia (p = 1.67 × 10−6; 4/280 cases vs 1/11,259 controls; Fisher exact test). All VPS16 patients showed mild progressive dystonia with writer's cramp as the presenting symptom between age 7 and 34 years (mean 20 years) that often progressed to generalized dystonia and was even accompanied by hyperkinetic movements and myoclonus in 1 patient.DiscussionOur data provide strong evidence for VPS16 pLoFs to be implicated in dystonia and knowledge on exon resolution expression levels as well as statistical measures proved to be useful for variant interpretation.

Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease

ObjectivesThe F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).MethodsEight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.ResultsThe female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38–57 years and had imaging and biomarker profiles similar to hers.DiscussionThe results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability

Background and ObjectivesTo investigate the pathogenicity of 2 novel KDM5C variations, report the clinical and neuroimaging findings, and review the available literature.MethodsPhysical examinations, structural neuroimaging studies, and exome sequence analysis were performed. KDM5C constructs were used to study the effect of the variations in transfected cells.ResultsWe identified 2 novel variations c.2233C>G and c.3392_3393delAG in the KDM5C gene harboring from 2 Chinese families with X-linked intellectual disability (ID). The affected male patients exhibited severe ID, short stature, and facial dysmorphism. The 1 with c.3392_3393delAG additionally had epilepsy and autistic spectrum disorder (ASD). Transiently transfected mutant KDM5C constructs both reduced protein expression and stability and decreased histone demethylase activities in cells. Reviewing the available literature, we found that the associated ASD tended to occur in patients with variations near the C-terminus of KDM5C.DiscussionWe report the clinical, molecular genetic, and pathologic features in patients with novel variations of KDM5C. The variability of the clinical phenotype in addition to an ID may associate with altered particular parts of KDM5C.

Pathogenic NOTCH3 Variants Are Frequent Among the Korean General Population

ObjectiveThis study aimed to determine the frequency of pathogenic NOTCH3 variants among Koreans.MethodsIn this cross-sectional study, we queried for pathogenic NOTCH3 variants in 2 Korean public genome databases: the Korean Reference Genome Database (KRGDB) and the Korean Genome Project (Korea1K). In addition, we screened the 3 most common pathogenic NOTCH3 variants (p.Arg75Pro, p.Arg544Cys, and p.Arg578Cys) for 1,000 individuals on Jeju Island, where the largest number of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported in Korea.ResultsThe pathogenic NOTCH3 variant (p.Arg544Cys) was found in 0.12% of sequences in the KRGDB, and 3 pathogenic variants (p.Arg75Pro, p.Arg182Cys, and p.Arg544Cys) were present in 0.44% of the Korea1K database. Of the 1,000 individuals on Jeju Island, we found 2 cysteine-altering NOTCH3 variants (p.Arg544Cys variant in 9 and p.Arg578Cys in 1 individual) in 1.00% of the participants (95% confidence interval: 0.48%–1.83%). The presence of cysteine-altering NOTCH3 variants was significantly associated with a history of stroke (p < 0.001).DiscussionPathogenic NOTCH3 variants are frequently found in the general Korean population. Such a high prevalence of pathogenic variants could threaten the brain health of tens of thousands to hundreds of thousands of older adults in Korea.