New Syndromes
De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes
A study published in the Human Molecular Genetics identified eight novel loss-of-function variants of KCNMA1. A phenotypic analysis of the patients carrying the recurrent de novo missense loss-of-function variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other loss-of-function variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria.
- Hum Mol Genet. 2019 Sep 1;28(17):2937-2951
A novel homozygous nonsense mutations in KLHL7 causes multiple dysmorphic features and developmental delay
A new study recently published in the European Journal of Medical Genetics identified two siblings with two siblings of Guatelmalan descent with a novel homozygous nonsense mutation in KLHL7. These children have multiple dysmorphic features and developmental delay. Recessive KLHL7 mutations are associated with a novel multisystem disease that featured various neurodevelopmental, musculoskeletal, dysmorphic, and other unique components. This report added to the clinical features and disease-associated variants of the newly-recognized spectrum of KLHL7 mutations.
- Eur J Med Genet. 2019 Sep;62(9):103551
Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome
A new study published in Nature Genetics evaluated seven unrelated individuals with a similar constellation of features that did not match any known syndrome. Hypopigmentation along Blaschko’s lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. This study showed that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies.
- Nat Genet. 2019 Sep 30
Loss of SMPD4 causes a developmental disorder characterized by microcephaly and congenital arthrogryposis
A recent study published in The American Journal of Human Genetics identified children from 12 unrelated families presenting with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3.
- Am J Hum Genet. 2019 Oct 3;105(4):689-705
DEGS1 variant causes neurological disorder
A new study published in the European Journal of Human Genetics identified four affected individuals with mild to severe intellectual disability, spastic quadriplegia, scoliosis and epilepsy in most, with no dysmorphic features. Whole exome sequencingidentified within this locus a single disease-associated homozygous variant in DEGS1, encoding C4-dihydroceramide desaturase, an enzyme of the ceramide synthesis pathway. This study described a sphingolipidosis causing a severe regressive neurological disease.
- Eur J Hum Genet. 2019 Nov;27(11):1668-1676
New Genes
Juvenile onset hereditary motor neuropathy is caused by nonsense mutations in alpha-II spectrin gene
- To read more about “Autosomal dominant distal hereditary motor neuropathy”
- Brain. 2019 Sep 1;142(9):2605-2616
Primary ciliary dyskinesia is caused by NME5 frameshift variant in Alaskan Malamutes
- To read more about “Primary ciliary dyskinesia”
- PLoS Genet. 2019 Sep 3;15(9):e1008378
Cystic fibrosis liver disease is caused by SERPINA1 Z allele
- To read more about “Cystic fibrosis”
- Genet Med. 2019 Sep;21(9):2151-2155
Recurrent respiratory papillomatosis is caused by an homozygous NLRP1 gain-of-function mutation
- To read more about “Recurrent respiratory papillomatosis”
- Proc Natl Acad Sci U S A. 2019 Sep 17;116(38):19055-19063
Familial dilated cardiomyopathy is caused by HAND2 loss-of-function mutation
- To read more about “Familial dilated cardiomyopathy”
- Eur J Med Genet. 2019 Sep;62(9):103540
Lissencephaly, subcortical heterotopia, and global developmental delay caused by bi-allelic loss of human APC2, encoding adenomatous polyposis coli protein 2
- Am J Hum Genet. 2019 Oct 3;105(4):844-853
A novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures caused by biallelic variants in COX4I1
- Am J Med Genet A. 2019 Oct;179(10):2138-2143
Intellectual disability and epilepsy caused by de novo substitutions of TRPM3
- Eur J Hum Genet. 2019 Oct; 27(10): 1611–1618
A variable neurodevelopmental disorder caused by de novo variants in CNOT3
- Eur J Hum Genet. 2019 Nov;27(11):1677-1682
Autosomal-recessive intellectual disability and microcephaly caused by bi-allelic variants in METTL5
- To read more about “Autosomal recessive primary microcephaly”
- Am J Hum Genet. 2019 Oct 3;105(4):869-878
Clinical Research
Multiple myeloma: A randomized study showed that consolidation with bortezomib after autologous stem cell transplantation in bortezomib-naive patients improved progression free survival without interfering with quality of life
- To read more about “Multiple myeloma”
- Blood. 2013 Jun 6;121(23):4647-54
Multiple Myeloma: A restrospective study showed that the progression free survival with upfront bortezomib, lenalidomide, and dexamethasone was longer compared to bortezomib, cyclophosphamide, and dexamethasone
- To read more about “Multiple myeloma”
- Eur J Haematol. 2019 Sep;103(3):247-254
Multiple myeloma : The phase 1b PAVO study showed that subcutaneous delivery of daratumumab was well tolerated in patients with relapsed or refractory multiple myeloma, and response rate consistent with IV daratumumab
- To read more about “Multiple myeloma”
- Blood. 2019 Aug 22;134(8):668-677
Advanced renal cell carcinoma: A study showed that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up
- To read more about “Renal cell carcinoma”
- Lancet Oncol. 2019 Oct;20(10):1370-1385
Renal cell carcinoma : A phase 2 study showed that individualised axitinib dosing in patients with metastatic renal cell carcinoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival
- To read more about “Renal cell carcinoma”
- Lancet Oncol. 2019 Oct;20(10):1386-1394
Progressive Desmoid tumours: A randomized phase 2 study (DESMOPAZ) showed that 83.7% of patients treated with pazopanib and 45% of patients treated with methotrexate-vinblastine chemotherapy had not progressed at 6 months
- To read more about “Desmoid tumor”
- Lancet Oncol. 2019 Sep;20(9):1263-1272
Squamous cell carcinoma of the oropharynx: A randomised phase 2 study showed that swallowing-related quality of life scores was superior with radiotherapy compared to transoral robotic surgery and neck dissection 1 year after treatment
- To read more about “Squamous cell carcinoma of the oropharynx”
- Lancet Oncol. 2019 Oct;20(10):1349-1359
Extraskeletal myxoid chondrosarcoma : A phase 2 study showed that pazopanib had clinically meaningful antitumour activity in patients with advanced extraskeletal myxoid chondrosarcoma
- To read more about “Extraskeletal myxoid chondrosarcoma”
- Lancet Oncol. 2019 Sep;20(9):1252-1262
Primary central nervous system lymphoma: A study showed the activity of IV infused tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma
- To read more about “Primary central nervous system lymphoma”
- Blood. 2019 Sep 12;134(11):860-866
Diffuse large B-cell lymphoma: Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL
- To read more about “Diffuse large B-cell lymphoma”
- Blood. 2019 Sep 26;134(13):1024-1036
Glioblastoma : A randomised phase 3 study showed the absence of changes in health-related quality of life and neurocognitive function and the survival benefit of lomustine-temozolomide versus temozolomide alone
- To read more about “Glioblastome”
- Lancet Oncol. 2019 Oct;20(10):1444-1453
Neuromyelitis optica : A double-blind, randomised placebo-controlled phase 2/3 trial showed that inebilizumab reduced the risk of attack
- To read more about “Neuromyelitis optica”
- Lancet. 2019 Oct 12;394(10206):1352-1363
Pyruvate kinase deficiency: A study showed that the administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with a sustained response during a median follow-up of 29 months
- To read more about “Hemolytic anemia due to red cell pyruvate kinase deficiency”
- N Engl J Med. 2019 Sep 5;381(10):933-944
Osteogenesis imperfecta : A phase 2 showed that compressive vertebrae of children could be effectively reshaped during zoledronic acid treatment
- To read more about “Osteogenesis imperfecta”
- Bone. 2019 Oct;127:164-171
Osteogenesis imperfecta : A multicenter North American study showed that relationships with mobility and bisphosphonates varied with osteogenesis imperfecta type and type used (oral/IV)
- To read more about “Osteogenesis imperfecta”
- Genet Med. 2019 Oct;21(10):2311-2318
Recessive dystrophic epidermolysis bullosa : A study showed that cultured epidermal autografts from clinically normal skin was a potentially well-tolerated treatment and the clinical effects persisted for at least 74 weeks after transplantation
- To read more about “Recessive dystrophic epidermolysis bullosa inversa”
- To read more about “Recessive dystrophic epidermolysis bullosa, generalized intermediate”
- J Invest Dermatol. 2019 Oct;139(10):2115-2124.e11
Niemann-Pick disease type C: A case report analysis showed the safety and potential benefit of systemic intravenous administration of hydroxypropyl-β-cyclodextrin to treat children and young adults
- To read more about “Niemann-Pick disease type C”
- Orphanet J Rare Dis. 2019; 14: 228
Syndrome d'Angelman: A placebo-controlled trial of folic acid and betaine in identical twins showed that the differences in the developmental testing results was not significant
- To read more about “Angelman syndrome”
- Orphanet J Rare Dis. 2019 Oct 22;14(1):232
PMM2-CDG: A study showed that postnatal intravenous D-mannose treatment seemed to be ineffective
- To read more about “PMM2-CDG”
- Orphanet J Rare Dis. 2019 Oct 22;14(1):231
22q11.2 deletion syndrome: A retrospective study in France of a cohort of 86 children showed that patients had a high rate of dysimmune manifestations and statistic correlations among CD4+ T-cell count, infectious manifestations, and autoimmunity
- To read more about “22q11.2 deletion syndrome”
- Am J Med Genet A. 2019 Nov;179(11):2207-2213
Therapeutic Approaches
Neurological muscular channelopathy due to a genetic ryanodine receptor defect: Mouse model of severe recessive RYR1-related myopathy represent a powerful model for establishing the pathomechanisms and pre-clinical testing of therapies
- To read more about “Neurological muscular channelopathy due to a genetic ryanodine receptor defect”
- Hum Mol Genet. 2019 Sep 15;28(18):3024-3036
Proteus syndrome: A study assessed the effectiveness of two method to model Proteus syndrome and evaluated the phenotype and variant distribution of Proteus syndrome mouse
- To read more about “Proteus syndrome”
- Hum Mol Genet. 2019 Sep 15;28(18):3024-3036
Osteogenesis imperfecta: Novel ActRIIB ligand trap increased muscle mass and improved bone geometry in a mouse model
- To read more about “Osteogenesis imperfecta”
- Bone. 2019 Nov;128:115036
Osteogenesis imperfecta : A novel transgenic murine model with persistently brittle bones simulating osteogenesis imperfecta type I
- To read more about “Osteogenesis imperfecta”
- Bone. 2019 Oct;127:646-655
CLN6 disease: Gene therapy corrected brain and behavioral pathologies in CLN6 disease
- To read more about “CLN6 disease”
- Mol Ther. 2019 Oct 2;27(10):1836-1847
CLN3 disease : Galactosylceramide improved behavioral, neuropathological, and biochemical parameters in mice model
- To read more about “CLN3 disease”
- Ann Neurol. 2019 Nov;86(5):729-742
Duchenne muscular dystrophy : Non-immunogenic utrophin gene therapy might be used to treat clinical dystrophin deficiency in muscular dystrophy animal models
- To read more about “Duchenne muscular dystrophy”
- Nat Med. 2019 Oct 7
Diagnostic Approaches
A retrospective review of multiple findings in diagnostic exome sequencing: half are distinct and half are overlapping diagnoses
- Genet Med. 2019 Oct;21(10):2199-2207
Systemic juvenile idiopathic arthritis : Development and initial validation of the MS score for diagnosis of macrophage activation syndrome
- To read more about “Systemic-onset juvenile idiopathic arthritis”
- Ann Rheum Dis. 2019 Oct;78(10):1357-1362
Autoinflammatory diseases : Current practices for the genetic diagnosis - results of a European Molecular Genetics Quality Network Survey
- Eur J Hum Genet. 2019 Oct;27(10):1502-1508
A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants with diseases of unknown etiology
- Am J Hum Genet. 2019 Oct 3;105(4):719-733
Disorders of somatic mosaicism: Diagnostic utility of next-generation sequencing - A five-year cumulative cohort
- Am J Hum Genet. 2019 Oct 3;105(4):734-746
Prenatal ultrasound findings of rasopathies in a cohort of 424 fetuses: update on genetic testing in the NGS era
- J Med Genet. 2019 Oct;56(10):654-661
From diagnostic yield to clinical impact: a pilot study on the implementation of prenatal exome sequencing in routine care
- Genet Med. 2019 Oct;21(10):2303-2310
Genetic regulatory variation in populations informs transcriptome analysis in rare disease
- Science. 2019 Oct 18;366(6463):351-356
Patient management and therapy
Improving the understanding of genetic variants in rare disease with large-scale reference populations
- JAMA. 2019 Aug 30. doi: 10.1001/jama.2019.12891
Myeloproliferative neoplasm: A review of advances in potential treatment options for myeloproliferative neoplasm associated myelofibrosis
- To read more about “Myeloproliferative neoplasm”
- Expert Opinion on Orphan Drugs 2019, 24 Sep 2019
Hematological disorders: A review of current challenges in gene therapy
- Gene Therapy volume 26, pages296–307 (2019)
Rare genetic skeletal diseases: A review of new therapeutic targets
- Expert Opin Orphan Drugs. 2015 Oct 3; 3(10): 1137–1154
Cerebellar malformations: A study showed that genetic defects impacted specific cerebellar cell types and confirmed a major contribution for non-genetic prenatal factors
- Am J Hum Genet. 2019 Sep 5;105(3):606-615
Mucopolysaccharidosis type 2: A study showed that aggregating case reports quantitatively, rather than analyzing them qualitatively, may improve conclusions in rare diseases and personalized medicine
- To read more about “Mucopolysaccharidosis type 2”
- Orphanet J Rare Dis. 2019 Oct 21;14(1):230
β-hemoglobinopathies: A review of lentiviral and genome-editing strategies for the treatment
- To read more about “Beta-thalassemia”
- To read more about “Sickle cell disease and related diseases”
- Blood. 2019 Aug 29
Primary immunodeficiency: A review of gene therapy
- To read more about “Primary immunodeficiency”
- Hum Mol Genet. 2019 Oct 1;28(R1):R15-R23
Hemoglobinopathies: A review of progress and future challenges in gene therapy
- To read more about “Hemoglobinopathy”
- Hum Mol Genet. 2019 Oct 1;28(R1):R24-R30
Lysosomal storage diseases : A review summarized the large animal models contributing to the development of therapies for central and peripheral nervous system dysfunction
- Hum Mol Genet. 2019 Oct 1;28(R1):R119-R131
Inherited neuromuscular diseases: A review of genetic approaches to the treatment
- Hum Mol Genet. 2019 Oct 1;28(R1):R55-R64
Muscular dystrophies: A review of AAV-based gene therapies
- Hum Mol Genet. 2019 Oct 1;28(R1):R102-R107
Cystic fibrosis lung disease : A review of advances in gene therapy
- To read more about “Cystic fibrosis”
- Hum Mol Genet. 2019 Oct 1;28(R1):R88-R94
Polycystic kidney disease: A review of novel treatments
- To read more about “Autosomal dominant polycystic kidney disease”
- To read more about “Autosomal recessive polycystic kidney disease”
- Hum Mol Genet. 2019 Oct 1;28(R1):R88-R94
22q11.2 deletion syndrome: A review of adverse effects of antipsychotic medication
- To read more about “22q11.2 deletion syndrome”
- Am J Med Genet A. 2019 Nov;179(11):2292-2306
Familial Mediterranean fever: Update on the management of colchicine resistant Familial Mediterranean fever
- To read more about “Familial Mediterranean fever”
- Orphanet J Rare Dis. 2019 Oct 15;14(1):224
Lynch syndrome: The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis
- To read more about “Lynch syndrome”
- Genet Med. 2019 Oct;21(10):2167-2180
Alkaptonuria : The potential of nitisinone for the treatment of alkaptonuria
- To read more about “Alkaptonuria”
- Expert Opin Orphan Drugs. 2019 Sep 4;7(10):435-441
Primary ciliary dyskinesia: A genetic disorder of motile cilia
- To read more about “Primary ciliary dyskinesia”
- Transl Sci Rare Dis. 2019;4(1-2):51-75
Recent advances in molecular therapies for neurological disease: triplet repeat disorders
- Hum Mol Genet. 2019 Oct 1;28(R1):R80-R87.
Recommendations
The use or generation of biomedical data and existing medicines to discover and establish new treatments for patients with rare diseases - recommendations of the IRDiRC data mining and repurposing task force
- Orphanet J Rare Dis. 2019 Oct 15;14(1):225
Turner syndrome: Recognition and management of adults from the transition of adolescence through the senior years
- To read more about “Turner syndrome”
- Am J Med Genet A. 2019 Oct;179(10):1987-2033
15q11.2 microdeletion syndrome: Estimating the effect size of the 15q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice
- To read more about “15q11.2 microdeletion syndrome”
- J Med Genet. 2019 Oct;56(10):701-710.
Lynch syndrome: The Manchester International Consensus Group recommendations for the management of gynecological cancers
- To read more about “Lynch syndrome”
- Genet Med. 2019 Oct;21(10):2390-2400
Epidemiology
Warsaw breakage syndrome: Study of carrier frequency in the Ashkenazi Jewish population and presentation of two cases
- To read more about “Warsaw breakage syndrome”
- Am J Med Genet A. 2019 Oct;179(10):2144-2151
Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries
- To read more about “Sarcoidosis”
- Eur Heart J. 2019 Oct 1;40(37):3121-3128
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