Genetics in Medicine最新文献

Purpose: RORA encodes the RAR-related orphan receptor-α (RORα), playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with RORA-related-neurodevelopmental disorder (RORA-NDD).

Methods: Forty individuals (30 unrelated; 10 siblings from 4 families) carrying RORA pathogenic/likely pathogenic variants were collected through an international collaboration.

Results: The 33 variants (29 de novo, 4 inherited, one shared), identified by genome/exome sequencing (n=21), chromosomal-microarray-analysis (n=7) or gene panels (n=4), included frameshift (n=18/33), missense (n=9/33) and stop-codon (n=6/33). Developmental disability (n=32/37), intellectual disability (n=22/32), and cerebellar signs (n=25/34) were the most striking clinical features. Cerebellar symptoms were divided into early-onset, late-onset and progressive subgroups. Cerebellar hypoplasia, atrophy, or both (n=16/25) were more frequent in individuals with missense variants in the DNA-binding-domain (DBD). Epilepsy (n=18/38), with prominent myoclonic seizure types (n=11/18), was classified in: i) genetic generalized epilepsy (n=10/18) with a syndromic diagnosis identifiable for six: epilepsy with eyelid myoclonia (n=5/6), epilepsy with myoclonic absence (n=1/6); ii) developmental and epileptic encephalopathy (n=5/18); and iii) unclassified (n=3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported.

Conclusion: Missense variants in DBD correlate to a more severe cerebellar phenotype. The RORA-NDD triad comprises developmental disability, cerebellar features and a spectrum of myoclonic epilepsy.

Purpose: Patients with neurodevelopmental disorders (NDDs) have high rates of neuropsychiatric comorbidities. Genomic medicine may help guide care because pathogenic variants are identified in up to 50% of patients with NDDs. We evaluate the impact of a genomics-informed, multidisciplinary, neuropsychiatric specialty clinic on the diagnosis and management of patients with NDDs.

Methods: We performed a retrospective study of 316 patients from the University of California, Los Angeles Care and Research in Neurogenetics Clinic, a genomics-informed multidisciplinary clinic.

Results: Among the 246 patients who underwent genetic testing, 41.8% had a pathogenic or likely pathogenic variant. Patients had 62 different genetic diagnoses, with 12 diagnoses shared by 2 or more patients, whereas 50 diagnoses were found in only single patients. Genetic diagnosis resulted in direct changes to clinical management in all patients with a pathogenic or likely pathogenic variant, including cascade testing (30.6%), family counseling (22.2%), medication changes (13.9%), clinical trial referral (2.8%), medical surveillance (30.6%), and specialty referrals (69.4%).

Conclusions: A genomics-informed model can provide significant clinical benefits to patients with NDDs, directly affecting management across multiple domains for most diagnosed patients. As precision treatments advance, establishing a genetic diagnosis will be critical for proper management. With the growing number of rare neurogenetic disorders, clinician training should emphasize core principles of genomic medicine over individual syndromes.

Purpose: Previous studies have established "red flags" that raise clinical suspicion for the hereditary form of transthyretin amyloidosis (ATTRv). However, these have not been specifically evaluated for the most common associated variant, TTR p.(Val142Ile).

Methods: Using an ancestrally diverse electronic health record-linked biobank with exome sequence data from 27,630 unrelated adults, we evaluated nine ATTRv-related clinical features among TTR p.(Val142Ile) positive and negative individuals.

Results: Among 337 variant positive individuals (median age 63, 60% female), ten (3.0%) were diagnosed with amyloidosis. TTR p.(Val142Ile) was associated with increased odds of cardiomyopathy/heart failure (CM/HF), atrial fibrillation, polyneuropathy, carpal tunnel syndrome, and proteinuria, but only in individuals ≥ 60 years. These features were evident 1.7 to 7.7 years earlier in variant positive vs. negative individuals (HR 1.37, P = 3.99 x 10^-2; HR 1.78, P = 2.52 x 10^-3; HR 1.78, P = 1.70 x 10^-3; HR 1.81, P = 5.14 x 10^-3; HR 1.60, P = 1.94 x 10^-2, respectively). By age 50, the cumulative incidence of CM/HF was 3.5-fold higher, and by age 60, the incidences of CM/HF, polyneuropathy, and proteinuria were 2-fold higher in variant positive individuals.

Conclusions: This study clarifies red flags that are associated with TTR p.(Val142Ile) in an age-dependent manner. With modifying therapies available, early diagnosis of ATTRv in variant positive individuals through recognition of key clinical features is paramount.

Purpose: To review biotinidase gene (BTD) variants identified in a large, diverse, reproductive carrier screening (RCS) cohort and outline management of heterozygotes with pathogenic or likely pathogenic (P/LP) variants.

Methods: This retrospective observational study included samples tested from January 2020 to September 2022 in a 274-gene panel. The study involved females aged 18 to 55 years. Screening was performed using next-generation sequencing covering exons and 10 base-pair flanking introns. The heterozygote frequency was calculated for P/LP variants for the entire population and individual racial/ethnic groups.

Results: Of the 91,637 women tested, 5625 (6.1%) had a P/LP variant in BTD. NM_000060.4:c.1330G>C p.(Asp444His) (referred to as D444H or D424H) alone, or in combination with another variant, accounted for 5193 (92.3%) of the positive tests. P/LP heterozygote rates differed between racial and ethnic groups. We ascertained 7 novel P/LP variants not previously recorded in databases.

Conclusion: The BTD P/LP variants identified through RCS were substantially compatible with those found through positive newborn screening. Therefore, RCS provides a potential for earlier diagnosis. We observed significant differences in P/LP heterozygote rates for biotinidase deficiency among different racial and ethnic groups. Most reported variants can be interpreted without requiring determination of serum biotinidase activity.

Purpose: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND.

Methods: We describe 19 patients with congenital CACNA1G-variants including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity.

Results: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics, and increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity.

Conclusion: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.

Purpose: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome or panel sequencing datasets aligned to a GRCh37, GRCh38, or T2T reference genome.

Methods: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has zero functional copies of SMN1.

Results: We developed SMA Finder and evaluated it on 16,626 exomes and 3,911 genomes from the Broad Institute Center for Mendelian Genomics, 1,157 exomes and 8,762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as Limb-girdle muscular dystrophy (LGMD).

Conclusion: Our extensive evaluation of SMA Finder on exome, genome and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, as well as the existence of treatment options, we propose that it is time to add SMN1 to the ACMG list of genes with reportable secondary findings after genome and exome sequencing.

Purpose: Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives.

Methods: We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays.

Results: All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement.

Conclusion: This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.

Purpose: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations.

Methods: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS.

Results: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases.

Conclusion: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.

Purpose: Exome sequencing (ES) and genome sequencing (GS) are useful tests to diagnose rare diseases in pediatric patients in critical care settings. Genomic test stewardship can increase the appropriate use of these tests leading to improved diagnostics and cost savings.

Methods: A mandatory review of ES and GS orders for admitted patients was implemented in March 2023. Outcomes of the reviews, cost analysis, and subsequent test results through February 2024 were analyzed with descriptive statistics.

Results: There were 444 genetic test request orders placed for 412 unique patients. Of these, 81 (18.2%) were redirected and 57 (12.8%) required modification after approval, leading to an overall cost savings of $345,821.00 or $778.88 per order. The combined diagnostic rate was 28.2% in this patient population.

Conclusion: Stewardship of ES/GS orders for pediatric inpatients is an effective tool to improve the appropriate usage of these genomic tests. Additional collaboration with stakeholders and expansion of genomic stewardship initiatives may shorten the diagnostic odyssey for critically ill pediatric patients and result in cost savings.

Purpose: Health care stakeholders' perspectives on the value of genomic testing vary widely and directly affect the access and practice of genomic medicine. To our knowledge, a review of US health care payers' perspectives on genomic testing has not been performed.

Methods: We conducted a systematic literature review of US payers' perspectives on genomic testing in the MEDLINE, PubMed, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Of the 161 nonduplicate records screened, we summarized findings from 20 included records, and using the framework method, common domains were recorded.

Results: Domains included clinical utility, coverage decision frameworks, potential harms, costs, paying for research, demand/pressure, the flexibility of outcomes considered, and personal utility. There was consensus on the definition of clinical utility as improved health outcomes, and the nuances of genomic testing were reported as challenging to fit within existing coverage decision frameworks. Perspectives varied on accepting broader outcomes or uses of genomic testing and whether costs influence coverage decisions. Study methodologies were heterogeneous.

Conclusion: A deeper understanding of how payers approach genomic testing may allow comparison with other stakeholders' perspectives and may identify challenges, opportunities, and solutions to align a conceptual and evidentiary framework better to demonstrate the value of genomic testing.