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Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact. We collected data from over 1.5 million genetic tests from 19 clinical laboratories across the United States and Canada from during 2020-2021. We found a lower rate of inconclusive results due to VUS on ES/GS tests compared to MGPs (22.5% vs. 32.6%; p

Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson’s disease and Parkinson’s disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD.

We aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.

IMPORTANCE: Nine hereditary neurodegenerative diseases are known as polyglutamine diseases, including Huntington disease, 6 spinocerebellar ataxias (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17), dentatorubral-pallidoluysion atrophy, and spinal bulbar muscular atrophy. OBJECTIVE: To determine the prevalence of carriers of intermediate and pathological polyglutamine disease–associated alleles among the general population. DESIGN, SETTING, AND PARTICIPANTS: This observational cross-sectional study included data from 5 large European population–based cohorts that were compiled between 1997 and 2012, and the analyses were conducted in 2018. In total, 16 547 DNA samples were obtained from participants of the 5 cohorts. Individuals with a lifetime diagnosis of major depression were excluded (n = 2351). In the remaining 14 196 participants without an established polyglutamine disease diagnosis, the CAG repeat size in both alleles of all 9 polyglutamine disease–associated genes (PDAGs) (ie, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR) was determined. EXPOSURE: The number of CAG repeats in the alleles of the 9 PDAGs. MAIN OUTCOMES AND MEASURES: The number of individuals with alleles within the intermediate or pathological range per PDAG, as well as differences in sex, age, and body mass index between individuals carrying alleles within the normal or intermediate range and individuals carrying alleles within the pathological range of PDAGs. RESULTS: In the 14 196 analyzed participants (age range, 18-99 years; 56.3% female), 10.7% had a CAG repeat number within the intermediate range of at least 1 PDAG. Moreover, up to 1.3% of the participants had a CAG repeat number within the disease-causing range, predominantly in the lower pathological range associated with elderly onset. No differences in sex, age, or body mass index were found between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range. CONCLUSIONS AND RELEVANCE: These results indicate a high prevalence of individuals carrying intermediate and pathological ranges of polyglutamine disease–associated alleles among the general population. Therefore, a substantially larger proportion of individuals than previously estimated may be at risk of developing a polyglutamine disease later in life or bearing children with a de novo mutation.

SummaryA CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.

Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.

Introduction We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes. Methods We diagnosed 22 affected individuals belonging to eight families and 43 sporadic cases with FTD in Apulia, Southern Italy, in 2 years. Mutations in common causative FTD genes ( GRN , MAPT , VCP , and TARDBP ) and C9ORF72 expansions were screened. Results Behavioral variant of FTD was the most common clinical subtype (50% and 69% in familial and sporadic cases, respectively). Social conduct impairment/disinhibition, loss of insight, and inflexibility were the most frequent clinical features observed at onset. One new mutation was identified in GRN in family A. Discussion Disease onset in sporadic FTD was more frequently characterized by a clustering of behavioral symptoms with apathy and loss of personal hygiene. Mutations in common causative FTD genes are not a major cause of familial and sporadic FTD in the Southern Italian population.

Background: Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with high clinical and genetic heterogeneity. In most cases, the cerebellar ataxia is not pure, and complicating clinical features such as pyramidal signs or extraneurological features are found. Objective: To identify the genetic origin of the cerebellar ataxia for 3 consanguineous North African families presenting with ARCA. Methods: Genome-wide high-density SNP genotyping and whole-exome sequencing were performed followed by Sanger sequencing for mutation confirmation. Results: Two variants were identified in SLC25A46. Mutations in this gene have been previously associated with Charcot-Marie-Tooth type 2 and optic atrophy. While the previously reported variant p.Arg340Cys seems to be consistently associated with the same clinical features such as childhood onset, optic atrophy, gait and speech difficulties, and wasting of the lower limbs, the patient with the novel mutation p.Trp160Ser did not present with optic atrophy and his ocular abnormalities were limited to nystagmus and saccadic pursuit. Conclusion: In this study, we report a novel variant (p.Trp160Ser) in SLC25A46 and we broaden the phenotypic spectrum associated with mutations in SLC25A46.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord. The survival motor neuron (SMN) gene has been identified as an SMA-determining gene. SMN exists as two copies in 5q13, and deletions in exons 7 and 8 of the telomeric copy (SMN(T)) occur in 95% of patients, regardless of disease severity. In a minority of patients, exon 7 but not exon 8 of SMN(T) appears deleted. We now report a patient with typical features of SMA type II who carried homozygous deletions of SMN(T) exon 7 and centromeric SMN (SMN(C)) exon 8 but retained SMN(T) exon 8 and SMN(C) exon 7. Sequence analysis demonstrated that SMN(C) exon 7 was adjacent to SMN(T) exon 8 on both SMN copies, indicating a double conversion. We confirm that sequence conversion is a common event in SMA and is associated with the milder form of the disease. The severity, however, can be modified in either positive or negative direction by other factors.

Ataxia with oculomotor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia caused by mutations in the SETX gene. It is a rare monogenic disease characterized by progressive cerebellar ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, and an elevated serum α-fetoprotein level. To date, >100 AOA2 patients have been described and 75 different mutations in the SETX gene have been identified. We report here the clinical and genetic findings of 13 AOA2 patients from 5 unrelated Tunisian consanguineous families. DNA was collected from probands and available family members, and the 24 SETX exons were screened by direct sequencing. Four different homozygous SETX gene mutations were identified. The missense mutation 915G>T [W305C] has been described previously in Algeria. The 3 other SETX mutations are novel, including a missense mutation c.7231C>T [R 2380 W], a nonsense mutation c.6475 C>T [R2098X], and a deletion c.7180-7183delAAAA [D2332fsX2343]. More extensive screening by molecular genetic analysis of SETX in patients with Friedreich ataxia-like phenotype may show that AOA2 is more common in Tunisia than previously thought.

Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. We studied three families diagnosed with ARCA.To determine the gene lesions responsible for their disorders, we performed high-density single-nucleotide polymorphism genotyping and exome sequencing.We identified a new mutation in the SACS gene and a known mutation in SPG11. Notably, we also identified a homozygous variant in APOB, a gene previously associated with ataxia.These findings demonstrate that exome sequencing is an efficient and direct diagnostic tool for identifying the causes of complex and genetically heterogeneous neurodegenerative diseases, early-stage disease or cases with limited clinical data.

Bardet-Biedl syndrome (BBS; MIM 209900) is a genetically heterogeneous autosomal recessive disorder characterized by progressive retinal degeneration, truncal obesity, cognitive impairment, polydactyly, hypogonadism, and renal anomalies.1–6 Among the nonconsanguineous populations of Northern Europe and America, the prevalence ranges from 1 in 100,000 in North America7 to 1 in 160,000 in Switzerland.8 BBS incidence increases within populations of high consanguinity or those that are geographically isolated.4,9,10 To date, 15 genes (BBS112, Meckel syndrome 1 [MKS1, BBS13], centrosomal protein 290 kDa/nephronophthisis 6 [CEP290/NPHP6, BBS14], and C2ORF86 [BBS15]) have been implicated in BBS.11,12 Mutations in these genes account only for approximately 70% of BBS patients, suggesting that there are additional genes to be found for BBS.13BBS1 and BBS10 are major pathogenic genes in European populations, each accounting for at least 20% of cases in most series.14,15 However, most other genes are rare contributors. For example, there is only a single documented family with mutations in each of BBS11 (TRIM32), BBS13 (MKS1), BBS14 (CEP290), and BBS15 (C2ORF86).12,16,17 A number of recent publications have expanded the spectrum of known BBS mutations,18–21 and suggested that mutations in some genes, including BBS13 and TMEM67/MKS3, can modify the expression of BBS phenotypes in patients who have mutations in other genes. BBS is also characterized by profound interfamilial and intrafamilial clinical variability, which is possibly explained in part by the presence of second-site modifiers. In some families, three mutated alleles in two BBS genes have been implicated (triallelic inheritance). BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS7, BBS8, and BBS10 have been implicated in triallelic inheritance of BBS,22–25 but the specific contribution of each allele is difficult to ascertain. Moreover, it has been suggested that there might be a connection between triallelism and the phenotypic severity of the disease.26 However, some studies have not identified a complex inheritance mode in this syndrome.27,28 In this study, we analyzed 55 families for known BBS genes (BBS1-BBS15) and identified 43 mutations in 46 families, 21 of which are novel. We also identified 7 Caucasian, 1 Arabic, and 1 Tunisian family in whom the molecular genetic findings raised the possibility of triallelic inheritance involving BBS1, BBS2, BBS3, BBS6, BBS7, BBS8, BBS9, BBS10, or BBS12. Although some sequence variations were identified in additional genes, no homozygous potential mutations were identified in previously unidentified BBS genes.

Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid β-glucosidase 1. β-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder. We studied four unrelated consanguineous families of Tunisian decent diagnosed with cerebellar ataxia of unknown origin. We performed homozygosity mapping and whole-exome sequencing in an attempt to identify the genetic origin of their disorder. We were able to identify mutations responsible for autosomal-recessive ataxia in these families within the gene encoding β-glucosidase 2, GBA2. Two nonsense mutations (c.363CA [p.Tyr121(∗)] and c.1018CT [p.Arg340(∗)]) and a substitution (c.2618GA [p.Arg873His]) were identified, probably resulting in nonfunctional enzyme. This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans.