Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome
Donkervoort S, Mohassel P, Laugwitz L, Zaki MS, Kamsteeg EJ, Maroofian R, Chao KR, Verschuuren-Bemelmans CC, Horber V, Fock AJM, McCarty RM, Jain MS, Biancavilla V, McMacken G, Nalls M, Voermans NC, Elbendary HM, Snyder M, Cai C, Lehky TJ, Stanley V, Iannaccone ST, Foley AR, Lochmüller H, Gleeson J, Houlden H, Haack TB, Horvath R, Bönnemann CG.
Am J Med Genet A. 2020 Oct;182(10):2272-2283. doi: 10.1002/ajmg.a.61765. Epub 2020 Aug 10.
ABSTRACT
Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.
PMID:
32776697 | PMC:
PMC7959540 | DOI:
10.1002/ajmg.a.61765
August 11, 2020
Correction to: Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies
Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, García-Cazorla A, Honzík T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thöny B, Scholl-Bürgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhánek J, Kuseyri Hübschmann O; International Working Group on Neurotransmitter related Disorders (iNTD).
Orphanet J Rare Dis. 2020 Aug 5;15(1):202. doi: 10.1186/s13023-020-01464-y.
ABSTRACT
An amendment to this paper has been published and can be accessed via the original article.
PMID:
32758270 | PMC:
PMC7409715 | DOI:
10.1186/s13023-020-01464-y
August 8, 2020
Clinician-centric diagnosis of rare genetic diseases: performance of a gene pertinence metric in decision support for clinicians
Segal MM, George R, Waltman P, El-Hattab AW, James KN, Stanley V, Gleeson J.
Orphanet J Rare Dis. 2020 Jul 22;15(1):191. doi: 10.1186/s13023-020-01461-1.
ABSTRACT
BACKGROUND: In diagnosis of rare genetic diseases we face a decision as to the degree to which the sequencing lab offers one or more diagnoses based on clinical input provided by the clinician, or the clinician reaches a diagnosis based on the complete set of variants provided by the lab. We tested a software approach to assist the clinician in making the diagnosis based on clinical findings and an annotated genomic variant table, using cases already solved using less automated processes.
RESULTS: For the 81 cases studied (involving 216 individuals), 70 had genetic abnormalities with phenotypes previously described in the literature, and 11 were not described in the literature at the time of analysis (“discovery genes”). These included cases beyond a trio, including ones with different variants in the same gene. In 100% of cases the abnormality was recognized. Of the 70, the abnormality was ranked #1 in 94% of cases, with an average rank 1.1 for all cases. Large CNVs could be analyzed in an integrated analysis, performed in 24 of the cases. The process is rapid enough to allow for periodic reanalysis of unsolved cases.
CONCLUSIONS: A clinician-friendly environment for clinical correlation can be provided to clinicians who are best positioned to have the clinical information needed for this interpretation.
PMID:
32698834 | PMC:
PMC7374885 | DOI:
10.1186/s13023-020-01461-1
July 24, 2020
Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair
Hanzlikova H, Prokhorova E, Krejcikova K, Cihlarova Z, Kalasova I, Kubovciak J, Sachova J, Hailstone R, Brazina J, Ghosh S, Cirak S, Gleeson JG, Ahel I, Caldecott KW.
Nat Commun. 2020 Jul 7;11(1):3391. doi: 10.1038/s41467-020-17069-9.
ABSTRACT
Neurodegeneration is a common hallmark of individuals with hereditary defects in DNA single-strand break repair; a process regulated by poly(ADP-ribose) metabolism. Recently, mutations in the ARH3 (ADPRHL2) hydrolase that removes ADP-ribose from proteins have been associated with neurodegenerative disease. Here, we show that ARH3-mutated patient cells accumulate mono(ADP-ribose) scars on core histones that are a molecular memory of recently repaired DNA single-strand breaks. We demonstrate that the ADP-ribose chromatin scars result in reduced endogenous levels of important chromatin modifications such as H3K9 acetylation, and that ARH3 patient cells exhibit measurable levels of deregulated transcription. Moreover, we show that the mono(ADP-ribose) scars are lost from the chromatin of ARH3-defective cells in the prolonged presence of PARP inhibition, and concomitantly that chromatin acetylation is restored to normal. Collectively, these data indicate that ARH3 can act as an eraser of ADP-ribose chromatin scars at sites of PARP activity during DNA single-strand break repair.
PMID:
32636369 | PMC:
PMC7341855 | DOI:
10.1038/s41467-020-17069-9
July 9, 2020
Neurogenomics
Diagnosis of cytomegalovirus infection from clinical whole genome sequencing
Ramchandar N, Ding Y, Farnaes L, Dimmock D, Hobbs C, Kingsmore SF, Bainbridge M.
Sci Rep. 2020 Jul 3;10(1):11020. doi: 10.1038/s41598-020-67656-5.
ABSTRACT
Rapid whole genome sequencing (rWGS) of peripheral blood has been used to detect microbial DNA in acute infections. Cytomegalovirus (CMV) is a herpesvirus capable of causing severe disease in neonates and immunocompromised patients. We identified CMV in patients undergoing diagnostic rWGS by matching reads that did not align to the human reference genome to a database of microbial genomes. rWGS was conducted on peripheral blood obtained from ill pediatric patients (age 1 day to 18 years). Reads not aligning to the human genome were analyzed using an in-house pipeline to identify DNA consistent with CMV infection. Of 669 patients who received rWGS from July 2016 through July 2019, we identified 28 patients (4.2%) with reads that aligned to the CMV reference genome. Six of these patients had clinical findings consistent with symptomatic CMV infection. Positive results were highly correlated (R
2 > 0.99, p < 0.001) to a CMV-qPCR assay conducted on DNA isolated from whole blood samples. In acutely ill children receiving rWGS for diagnosis of genetic disease, we propose analysis of patient genetic data to identify CMV, which could impact treatment of up to 4% of children in the intensive care unit.
PMID:
32620939 | PMC:
PMC7335102 | DOI:
10.1038/s41598-020-67656-5
July 5, 2020
Gene DiscoveryrWGS
Commentary
Kingsmore SF.
Clin Chem. 2020 Jan 1;66(1):51-52. doi: 10.1093/clinchem.2019.310037.
Comment on
PMID:
32609850 | DOI:
10.1093/clinchem.2019.310037
July 2, 2020
Failure to thrive – an overlooked manifestation of KMT2B-related dystonia: a case presentation
Ng A, Galosi S, Salz L, Wong T, Schwager C, Amudhavalli S, Gelineau-Morel R, Chowdhury S; Rady Children’s Institute for Genomic Medicine Investigators, Friedman J.
BMC Neurol. 2020 Jun 16;20(1):246. doi: 10.1186/s12883-020-01798-x.
ABSTRACT
BACKGROUND: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this non-neurologic, but consequential impact of mutation in this gene.
CASE PRESENTATION: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned.
CONCLUSION: Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members.
PMID:
32546208 | PMC:
PMC7296679 | DOI:
10.1186/s12883-020-01798-x
June 18, 2020
Genetic Neurologic DiseaseNeurogenomicsRare Disease
Adaptive functioning in children and adolescents with Trisomy X: An exploratory analysis
Wigby K, Cordeiro L, Wilson R, Angkustsiri K, Simon TJ, Tartaglia N.
Am J Med Genet C Semin Med Genet. 2020 Jun;184(2):456-468. doi: 10.1002/ajmg.c.31803. Epub 2020 Jun 17.
ABSTRACT
Identifying the factors related to adaptive functioning will improve the information available to families and providers of females with Trisomy X. Cognitive and behavioral features were assessed in 50 females ages 12.2 ± 3.6 years using the Behavior Assessment System for Children Second Edition (BASC-2) and Wechsler Scales of Intelligence. Executive functioning, social skills, and autistic traits were evaluated in a subset. Adaptive functioning was assessed using the BASC-2 adaptive skills composite score (ASC). Participants were classified as average adaptive skills (ASC T-score > 40) or deficits (ASC T-score < 40). Group comparisons were conducted. Multiple linear regression examined which factors contributed to ASC score. Twenty-eight females (55.6%) had adaptive skills deficits with functional communication being the most commonly affected adaptive domain. The group with ASC in the average range had higher verbal IQ (VIQ) and lower rates of numerous behavioral concerns. Internalizing behavior composite, DSM-IV inattentive symptoms score, and VIQ were significant predictors of ASC. Prenatally diagnosed females comprised over 70% of those with average adaptive skills. In this study, internalizing behaviors, inattentive ADHD symptoms, and VIQ were associated with poorer adaptive functioning. Early interventions targeting internalizing behaviors, attention/executive functioning, and communication skills may improve adaptive skills and deserve further study.
PMID:
32548885 | DOI:
10.1002/ajmg.c.31803
June 18, 2020
Genetic testing strategies in the newborn
Carroll J, Wigby K, Murray S.
J Perinatol. 2020 Jul;40(7):1007-1016. doi: 10.1038/s41372-020-0697-y. Epub 2020 May 29.
ABSTRACT
Genetic disorders presenting in the neonatal period can have a significant impact on morbidity and mortality. Early diagnosis can facilitate timely prognostic counseling to families and possibility of precision care, which could improve outcome. As availability of diagnostic testing expands, the required knowledge base of the neonatologist must also expand to include proper application and understanding of genetic testing modalities, especially where availability of clinical genetics consultation is limited. Herein, we review genetic tests utilized in the neonatal intensive care unit (NICU) providing background on the technology, clinical indications, advantages, and limitations of the tests. This review will span from classic cytogenetics to the evolving role of next generation sequencing and its impact on the management of neonatal disease.
PMID:
32472107 | DOI:
10.1038/s41372-020-0697-y
May 31, 2020
The Medical Genome Initiative: moving whole-genome sequencing for rare disease diagnosis to the clinic
Marshall CR, Bick D, Belmont JW, Taylor SL, Ashley E, Dimmock D, Jobanputra V, Kearney HM, Kulkarni S, Rehm H; Medical Genome Initiative.
Genome Med. 2020 May 27;12(1):48. doi: 10.1186/s13073-020-00748-z.
ABSTRACT
Clinical whole-genome sequencing (WGS) offers clear diagnostic benefits for patients with rare disease. However, there are barriers to its widespread adoption, including a lack of standards for clinical practice. The Medical Genome Initiative consortium was formed to provide practical guidance and support the development of standards for the use of clinical WGS.
PMID:
32460895 | PMC:
PMC7254704 | DOI:
10.1186/s13073-020-00748-z
May 29, 2020
Rare Disease
