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Edition of 22 December 2021

New Syndromes

TNPO2 loss of function associate with human developmental delays, neurologic deficits, and dysmorphic features, and alter TNPO2 activity in Drosophila

A new study published in the American Journal of Human Genetics, identified mutations in the gene coding for TNPO2 (transportin-2), within fifteen individuals who express a global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. Functional studies with orthologous gene in drosophila show that total, or progressive, loss of transportin activity causes developmental defects, and show links with ectopically expression, and effect of variants position.

DDX23 loss of function associate with syndromic neurodevelopmental disorder

A new study published in the American Journal of Human Genetics identified missense variants in the gene coding for DDX23 (an RNA helicase), within nine unrelated individuals (gathered through GeneMatcher) who express tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, seizures, and a variety of other symptoms (in the skeletal, renal, ocular, and cardiac systems).

PI4KA loss of function cause a neurodevelopmental syndrome with hypomyelinating leukodystrophy

A new study published in Brain identified biallelic mutations in the gene coding for PI4KA (a phosphoinositide kinase), within ten unrelated individuals who express a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses highlight the importance of phosphoinositide signalling in human brain development and the myelin sheath (in this case through fibroblasts and peripheral blood mononuclear cells).

Brain . 2021 Oct 22;144(9):2659-2669

CCND2 proximal variants associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes

A new study published in the American Journal of Human Genetics identified variants (frameshift ones, and a dominantly inherited stop-gain one) in the gene coding for the distal part of CCND2 (a critical cell cycle regulator, and key member of a cyclin complex), within five individuals (from three unrelated families) who express microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. This seems to be the first reported association between proximal CCND2 variants and microcephaly. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes.

Am J Med Genet A . 2021 Sep;185(9):2719-2738

SPATA5L1 loss of function lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

A new study published in the American Journal of Human Genetics identified 28 biallelic variants in SPATA5L1 (a protein: spermatogenesis-associated 5 like 1), within 47 individuals (from 26 unrelated families, and 2 related ones) who express sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) present microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Complementary researches (modeling, brain imaging, immunofluorescent imaging in rat, transcriptomic analysis on fibroblasts) indicate these mutations lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Am J Hum Genet . 2021 Oct 7;108(10):2006-2016

New Genes

Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

To read more about “Juvenile amyotrophic lateral sclerosis”

JAMA Neurol . 2021 Oct 1;78(10):1236-1248

Bi-allelic mutations of DNAH10 cause primary male infertility with asthenoteratozoospermia in humans and mice

To read more about “Male infertility with teratozoospermia due to single gene mutation”

Am J Hum Genet . 2021 Aug 5;108(8):1466-1477

Biallelic P4HTM variants associated with HIDEA syndrome and mitochondrial respiratory chain complex I deficiency

To read more about “Isolated complex I deficiency”

Eur J Hum Genet . 2021 Oct;29(10):1536-1541

De novo mutations of SCN1A are responsible for arthrogryposis broadening the SCN1A -related phenotypes

To read more about “Arthrogryposis multiplex congenita”

J Med Genet . 2021 Nov;58(11):737-742

Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia

To read more about “Autosomal dominant pure spastic paraplegia”

Ann Neurol . 2021 Nov;90(5):738-750

ERBB4 exonic deletions on chromosome 2q34 in patients with intellectual disability or epilepsy

To read more about “Autosomal dominant non-syndromic intellectual disability”

Eur J Hum Genet . 2021 Sep;29(9):1377-1383

Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

To read more about “Pontocerebellar hypoplasia type 1”

Eur J Hum Genet . 2021 Sep;29(9):1348-1353

Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders.

To read more about “Autosomal recessive primary microcephal”
To read more about “Seckel syndrome”

Hum Mol Genet . 2021 Nov 1;30(22):2068-2081

Clinical Research

Variability of treatment modalities and intensity in patients with severe haemophilia A on prophylaxis: Results from the Italian national registry

To read more about “Hemophilia A”

Eur J Haematol . 2021 Oct;107(4):408-415

Therapeutic approach to pediatric patients with acute chest syndrome: national multicenter survey of non invasive ventilation (NIV) and transfusion: NIV for pediatric acute chest syndrome

To read more about “Sickle cell anemia”

Arch Pediatr . 2021 Oct;28(7):559-566

Survival outcomes of very low birth weight infants with trisomy 18

To read more about “Trisomy 18”

Am J Med Genet A . 2021 Nov;185(11):3459-3465

Spondyloepimetaphyseal dysplasia EXTL3-deficient type: Long-term follow-up and review of the literature

To read more about “Skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome”

Am J Med Genet A . 2021 Oct;185(10):3104-3110

Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases

To read more about “Prolidase deficiency”

Genet Med . 2021 Sep;23(9):1604-1615

Quality indicators for systemic lupus erythematosus based on the 2019 EULAR recommendations: Development and initial validation in a cohort of 220 patients

To read more about “Systemic lupus erythematosus”

Ann Rheum Dis . 2021 Sep;80(9):1175-1182.

Prospective Study of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma on Waitlist for Liver Transplant

To read more about “Hepatocellular carcinoma”

Hepatology . 2021 Nov;74(5):2580-2594

Pneumonia and respiratory infection in Down syndrome: A 10-year cohort analysis of inpatient and outpatient encounters across the lifespan

To read more about “Down syndrome”

Am J Med Genet A . 2021 Oct;185(10):2878-2887

Physical therapy treatment of hypermobile Ehlers–Danlos syndrome: A systematic review

To read more about “Hypermobile Ehlers-Danlos syndrome”

Am J Med Genet A . 2021 Oct;185(10):2986-2994

Optimizing the Start Time of Biologics in Polyarticular Juvenile Idiopathic Arthritis: A Comparative Effectiveness Study of Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans

To read more about “Polyarticular juvenile idiopathic arthritis”

https://pubmed.ncbi.nlm.nih.gov/34105312/

Lyme neuroborreliosis in pediatrics: A retrospective, descriptive study in southwest France

To read more about “Lyme disease”

Arch Pediatr . 2021 Oct;28(7):537-543

Long-term tolerability and efficacy after initial PegIFN-α addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study

To read more about “Chronic myeloid leukemia”

Eur J Haematol . 2021 Dec;107(6):617-623

Long-term outcome in patients with follicular lymphoma following high-dose therapy and autologous stem cell transplantation

To read more about “Follicular lymphoma”

Eur J Haematol . 2021 Nov;107(5):543-552

Impact of time to diagnosis on Mayo stages, treatment outcome, and survival in patients with AL amyloidosis and cardiac involvement

To read more about “Aggressive B-cell non-Hodgkin lymphoma”

Eur J Haematol . 2021 Oct;107(4):449-457

Immunomodulatory Medication Use in Newly Diagnosed Youth With Systemic Lupus Erythematosus

To read more about “Systemic lupus erythematosus”

Arthritis Care Res (Hoboken) . 2021 Nov;73(11):1672-1677

Multiple myeloma (CASSIOPEIA; open-label, randomised): phase 3 trial, "coktail (bortezomib, thalidomide, dexamethasone) +/- "daratumumab" for autologous stem-cell transplant.

To read more about “Multiple myeloma”

Lancet Oncol . 2021 Oct;22(10):1378-1390

Response to Letter to the Editor From L. Sävendahl et al: “Weekly Lonapegsomatropin in Treatment-Naïve Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial”

Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies

To read more about “Congenital adrenal hyperplasia”

J Clin Endocrinol Metab . 2021 Oct 21;106(11):e4666-e4679

Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

To read more about “GNE myopathy”

Genet Med . 2021 Nov;23(11):2067-2075

Biomarkers

Ultrasound halo sign as a potential monitoring tool for patients with giant cell arteritis: A prospective analysis

To read more about “Giant cell arteritis”

Ann Rheum Dis . 2021 Nov;80(11):1475-1482

Is ghrelin a biomarker of early-onset scoliosis in children with Prader–Willi syndrome?

To read more about “Prader-Willi syndrome”

Orphanet J Rare Dis . 2021 Jul 8;16(1):305

Diagnostic Approaches

Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)

Therapeutic Approaches

A factor VIIIa–mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice

To read more about “Hemophilia A”

Blood . 2021 Oct 7;138(14):1258-1268

A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models

To read more about “Acute myeloid leukemia”

Sci Transl Med . 2021 Sep 29;13(613):eabj1578

Analysis and Validation of Human Targets and Treatments Using a Hepatocellular Carcinoma–Immune Humanized Mouse Model

To read more about “Hepatocellular carcinoma”

Hepatology . 2021 Sep;74(3):1395-1410

BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma

To read more about “Glioblastoma”

Mol Ther . 2021 Oct 6;29(10):3011-3026

Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma

To read more about “Hepatocellular carcinoma”

Gut . 2021 Sep;70(9):1746-1757

CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington’s disease

To read more about “Huntington disease”

Sci Transl Med . 2021 Sep 29;13(613):eabe7104

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and down syndrome

To read more about “Down syndrome”

PLoS Genet . 2021 Sep 29;17(9):e1009777

Full-length dystrophin restoration via targeted exon integration by AAV-CRISPR in a humanized mouse model of Duchenne muscular dystrophy

To read more about “Duchenne muscular dystrophy”

Mol Ther . 2021 Nov 3;29(11):3243-3257

Immunomodulatory Effects of Lenvatinib Plus Anti–Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma

To read more about “Hepatocellular carcinoma”

Hepatology . 2021 Nov;74(5):2652-2669

Patient Management and Therapy

A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations

Orphanet J Rare Dis . 2021 Jul 8;16(1):306

Adult rheumatologic features, treatment and complications of X-linked hypophosphatemia

To read more about “X-linked hypophosphatemia”

Arch Pediatr . 2021 Oct;28(7):606-611

CRISPR technologies for the treatment of Duchenne muscular dystrophy

To read more about “Duchenne muscular dystrophy”

Mol Ther . 2021 Nov 3;29(11):3179-3191

Establishing a second-generation artificial intelligence-based system for improving diagnosis, treatment, and monitoring of patients with rare diseases

Eur J Hum Genet . 2021 Oct;29(10):1485-1490

GATA2 deficiency syndrome: A decade of discovery

To read more about “Monocytopenia with susceptibility to infections”
To read more about “Inherited acute myeloid leukemia”
To read more about “Deafness-lymphedema-leukemia syndrome”

Hum Mutat . 2021 Nov;42(11):1399-1421

Epidemiology

Demographic, clinical, and ancestry characterization of a large cluster of mucopolysaccharidosis IV A in the Brazilian Northeast region

To read more about “Mucopolysaccharidosis type 4”

Am J Med Genet A . 2021 Oct;185(10):2929-2940

Genetic epidemiology approach to estimating birth incidence and current disease prevalence for rhizomelic chondrodysplasia punctata

To read more about “Rhizomelic chondrodysplasia punctata”

Orphanet J Rare Dis . 2021 Jul 6;16(1):300

Incidence and short-term outcomes of Kawasaki disease

To read more about “Kawasaki disease”

Pediatr Res . 2021 Sep;90(3):670-677

International Increases in Merkel Cell Carcinoma Incidence Rates between 1997 and 2016

To read more about “Cutaneous neuroendocrine carcinoma”

J Invest Dermatol . 2021 Nov;141(11):2596-2601.e1

Quality of Life

Cognitive and behavioral risk factors for low quality of life in survivors of childhood acute lymphoblastic leukemia

To read more about “Acute lymphoblastic leukemia”

Pediatr Res . 2021 Aug;90(2):419-426

Functional Ability and Health-Related Quality of Life in Randomized Controlled Trials of Tocilizumab in Patients With Juvenile Idiopathic Arthritis

To read more about “Juvenile idiopathic arthritis”

Arthritis Care Res (Hoboken) . 2021 Sep;73(9):1264-1274

Summary of the edition of 22 December 2021

Editorial
Political news
Scientific news
And also...