Edition of 25 November 2025 - Newsletter - OrphaNews

New Syndromes

CDDC88A variants cause malformations of cortical development and immune dysfunction

A new study published in Human Molecular Genetics characterized a heterozygous missense variant and intragenic deletion in the CCDC88A gene, coding for a girdin which is closely linked to many cellular functions (for example actin remodeling and cell proliferation) as a multi-modular scaffolding protein. The variants were found among 2 siblings, suffering from malformations of cortical development (MCD) and a severe neurological phenotype (microcephaly, epilepsy, intellectual disability), and susceptibility to infections. Various analyses showed an altered immunity and girdin-related cellular changes, such as cell morphology and proliferation-migration dichotomy, in both patient and knockout fibroblasts, reinforcing the pathogenic relevance of these variants and underlining the importance of considering the CCDC88A gene in the diagnosis of MCDs.

Hum Mol Genet. 2025 Jul 20;34(15):1294-1312

DDX39B variants cause a neurodevelopmental syndrome

A new study published in Brain described de novo missense variants or inherited splice-altering variants in DDX39B, which encodes an RNA helicase playing a key role in mRNA physiology (including pre-mRNA splicing, nuclear export, ribosome assembly and translation initiation) as a core component of the TRanscription-EXport (TREX) super protein complex. The variants were found among 6 individuals from 5 unrelated families, presenting with mild to severe developmental delay, intellectual disability, hypotonia, histories of epilepsy or seizure, short stature, skeletal abnormalities and variable dysmorphic features. Various analyses confirmed the role of DDX39B in several protein and RNA interactions and identified DDX39B deficiency, as an additional type of the new TREX-complex-related entity, leading to neurodevelopmental syndrome.

Brain. 2025 Aug 1;148(8):2658-2670

K2M2B variants cause a distinct epigenetic neurodevelopmental disorder

A new study published in Human Molecular Genetics described variants in K2M2B, which is involved in epigenetic regulation. The variants were found among 9 individuals with developmental delays, mainly in the speech and motor domain, variable intellectual disability, congenital heart defects and facial dysmorphism. Other variable findings observed were musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Various analyses confirmed the role of K2M2B as a crucial player in epigenetic regulation through its DNA-binding ability in the CxxC domain.

Hum Mol Genet. 2025 Aug 16;34(16):1353-1367

TBCE variants cause a novel distinct mild TBCE-associated phenotype

A new study published in The Journal of Clinical Endocrinology & Metabolism characterized homozygous or compound heterozygous variants in TBCE, which encodes an essential component of the microtubule assembly machinery as part of tubulin-bonding cofactors (TBCs). The variants were found among 7 individuals with a mild TBCE-associated phenotype. Distinct from the three other TBCE-related disorders already described in the literature, this new phenotype comprises amyotrophy, testicular failure, and mild intellectual disability with or without short stature as the main features. Various analyses uncover complex molecular mechanisms contributing to the milder phenotype in these patients, providing insights into a new TBCE-related disorder.

New Genes

Autosomal dominant cerebellar ataxia: Identification of heterozygous variants in RAB3A

To read more about “Autosomal dominant cerebellar ataxia”

Brain. 2025 Aug 1;148(8):2812-2826

Beckwith-Wiedemann syndrome: Identification of biallelic variants in UHRF1

To read more about “Beckwith-Wiedemann syndrome”

Proc Natl Acad Sci USA . 2025 Aug 26;122(34):e2505884122

Congenital myasthenic syndrome: Identification of a biallelic loss-of-function variant in UNC50

To read more about “Congenital myasthenic syndrome”

Am J Med Genet A. 2025 Aug;197(8):e64086

Genetic recurrent myoglobinuria: Identification of a heterozygous missense variant in ATP2A2

To read more about “Genetic recurrent myoglobinuria”

Brain. 2025 Aug 1;148(8):2869-2882

Non-specific syndromic intellectual disability: Identification of heterozygous variants in BMAL1

To read more about “Non-specific syndromic intellectual disability”

Proc Natl Acad Sci USA. 2025 Aug 5;122(31):e2427085122

Progressive symmetric erythrokeratodermia: Identification of a de novo missense variant in EMP2

To read more about “Progressive symmetric erythrokeratodermia”

Proc Natl Acad Sci USA. 2025 Aug 12;122(32):e2509896122

Clinical Research

Tuberous sclerosis complex: Identification of four reproducible and distinct clusters of disease phenotypes (natural history)

To read more about “Tuberous sclerosis complex”

Brain. 2025 Aug 1;148(8):2912-2919

Glycogen storage disease due to acid maltase deficiency, late-onset: Effectiveness of three enzyme replacement therapies compared to each other and to best supportive care (systematic reveiw and meta-analysis)

To read more about “Glycogen storage disease due to acid maltase deficiency, late-onset”

Orphanet J Rare Dis. 2025 Aug 21;20(1):451

Fabry disease: Reduction in plasmatic disease biomarkers, improvement in symptoms, and stabilization of kidney function by well-tolerated agalsidase beta in Chinese patients (phase 4 trial)

To read more about “Fabry disease”

Orphanet J Rare Dis. 2025 Aug 4;20(1):401

Phenylketonuria: Development of a staged therapeutic approach for use of pegvaliase to achieve clinically meaningful blood Phe targets based on a pharmacokinetic/pharmacodynamic model (extension of phase 3 trials)

To read more about “Phenylketonuria”

Genet Med. 2025 Aug;27(8):101459

Other publications

Please find below some more interesting publications

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Natural history

Congenital diaphragmatic hernia Isolated congenital diaphragmatic hernia and three-year neurodevelopmental outcomes

Pediatr Res. 2025 Aug;98(2):690-696

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Registry

Long-term survival and cure fraction estimates for paediatric central nervous system tumours in 31 European countries (EUROCARE-6): a population-based study

Lancet Oncol. 2025 Aug;26(8):1091-1099

Congenital adrenal hyperplasia Delineating the Psychiatric Morbidity Spectrum in Congenital Adrenal Hyperplasia: A Population-based Registry Study

J Clin Endocrinol Metab. 2025 Jul 15;110(8):2147-2156

Homozygous familial hypercholesterolemia Homozygous Familial Hypercholesterolemia in Spain: Data From Registry of the Spanish Atherosclerosis Society

J Clin Endocrinol Metab. 2025 Jul 15;110(8):2280-2287

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Large observational study

Familial cerebral cavernous malformation Lifetime Risk of First Symptomatic ICH or Seizure in Familial Cerebral Cavernous Malformations: A Multicenter Patient Data Analysis

Neurology. 2025 Aug 12;105(3):e213798

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Clinical trial

Autoimmune pulmonary alveolar proteinosis Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis

N Engl J Med. 2025 Aug 21;393(8):764-773

Congenital isolated hyperinsulinism Dasiglucagon in Children With Congenital Hyperinsulinism Up to 1 Year of Age: Results From a Randomized Clinical Trial

J Clin Endocrinol Metab. 2025 Jul 15;110(8):e2674-e2681

Eosinophilic granulomatosis with polyangiitis Long-Term Safety and Efficacy of Mepolizumab in Eosinophilic Granulomatosis With Polyangiitis

Arthritis Rheumatol. 2025 Aug;77(8):1052-1062

Immune thrombocytopenia Multicenter Single-Blind Randomized Controlled Trial of the Romiplostim Biosimilar

EJHaem. 2025 Jul 24;6(4):e70105

Mucopolysaccharidosis type 2 Efficacy and safety of idursulfase beta in the treatment of mucopolysaccharidosis II: A phase-3, 2-part study compared with a historical placebo cohort

Genet Med. 2025 Aug;27(8):101460

Non-acquired isolated growth hormone deficiency A Novel Y-Shaped Pegylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency

J Clin Endocrinol Metab. 2025 Jul 15;110(8):e2605-e2613

Proximal spinal muscular atrophy Risdiplam in Presymptomatic Spinal Muscular Atrophy

N Engl J Med. 2025 Aug 14;393(7):671-682

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Real world evidence

Gaucher disease Evaluation and study of adverse reactions to imiglucerase based on the FAERS database

Orphanet J Rare Dis. 2025 Aug 7;20(1):406

Therapeutic Approaches

Amyotrophic lateral sclerosis: Significant lifespan extension and improved neurodegenerative outcomes through SOD1 reduction with chemically stabilized siRNA in disease mouse model

To read more about “Amyotrophic lateral sclerosis”

Mol Ther. 2025 Aug 6;33(8):3917-3938

Duchenne muscular dystrophy: Significant functional improvements of key dystrophic hallmarks based on a template-assisted sequence knockin (TASK) strategy in a deletion murine model

To read more about “Duchenne muscular dystrophy”

Mol Ther. 2025 Aug 6;33(8):3733-3745

STXBP1-related encephalopathy: Developement of a well-tolerated neuron-targeted gene therapy to rescue multiple disease phenotypes in mice and nonhuman primates

To read more about “STXBP1-related encephalopathy”

Mol Ther. 2025 Aug 6;33(8):3822-3840

Other publications

Please find below some more interesting publications

22q11.2 duplication syndrome Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome

Sci Transl Med. 2025 Aug 20;17(812):eads2116

Acute graft versus host disease A single dose of a CD137 antibody-drug conjugate protects rhesus macaque allogeneic HCT recipients against acute GVHD

Blood. 2025 Aug 28;146(9):1127-1141

Autosomal dominant Charcot-Marie-Tooth disease type 2E The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E

Hum Mol Genet. 2025 Jul 20;34(15):1313-1327

Friedreich ataxia Alpha-lipoic acid supplementation improves pathological alterations in cellular models of Friedreich ataxia

Orphanet J Rare Dis. 2025 Aug 23;20(1):453

Gaucher disease type 1 FLT201, a novel liver-directed AAV gene therapy candidate for Gaucher disease type 1

Mol Ther. 2025 Aug 6;33(8):3789-3807

Metachromatic leukodystrophy Cross-species efficacy of AAV-mediated ARSA replacement for metachromatic leukodystrophy

J Clin Invest. 2025 Jun 19;135(16):e185001

Pemphigus vulgaris Antigen-Fc fusion therapy reduces severity of a model of pemphigus vulgaris without systemic immunosuppression

Sci Transl Med. 2025 Aug 27;17(813):eadk6484

Systemic sclerosis Antifibrotic effects of specific targeting of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in murine models and ex vivo models of scleroderma skin

Arthritis Rheumatol. 2025 Aug;77(8):1063-1076

Tay-Sachs disease CNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice

J Clin Invest. 2025 Jun 17;135(16):e183434

Biomarkers

Congenital diaphragmatic hernia: Feasibility of urinary N-terminal pro-brain natriuretic peptide (NT-proBNP) as a non-invasive biomarker to assess pulmonary hypertension and cardiac dysfunction

To read more about “Congenital diaphragmatic hernia”

Pediatr Res. 2025 Jun;97(7):2305-2311

Other publications

Please find below some more interesting publications

Down syndrome Prediction of amyloid and tau brain deposition and cognitive decline in people with Down syndrome using plasma biomarkers: a longitudinal cohort study

Lancet Neurol. 2025 Jul;24(7):591-600

Duchenne and Becker muscular dystrophy Interleukin-17B is a new biomarker of human muscle regeneration in dystrophinopathies

Brain. 2025 Jul 7;148(7):2579-2591

Familial Mediterranean fever Serum endocan, asymmetric dimethylarginine and lipid profile in children with familial Mediterranean fever

Pediatr Res. 2025 Jun;97(7):2312-2317

Langerhans cell histiocytosis BRAF V600E-positive mononuclear cells in blood at diagnosis portend treatment failure and neurodegeneration in pediatric LCH

Blood. 2025 Jul 10;146(2):206-218

Limited cutaneous systemic sclerosis Serum Type I Interferon Score for Prediction of Clinically Meaningful Disease Progression in Limited Cutaneous Systemic Sclerosis

Arthritis Rheumatol. 2025 Jul;77(7):929-941

Systemic lupus erythematosus Novel IgG and IgA autoantibodies validated in two independent cohorts are associated with disease activity and determine organ manifestations in systemic lupus erythematosus: implications for anti-LIN28A, anti-HMGN5, anti-IRF5, and anti-TGIF1

Ann Rheum Dis. 2025 Jul;84(7):1164-1179

Diagnostic Approaches

Hereditary angioedema: Example of proactive diagnosis by an electronic medical record-based system

To read more about “Hereditary angioedema”

Orphanet J Rare Dis. 2025 Jul 28;20(1):386

Other publications

Please find below some more interesting publications

Improved diagnosis of patients with rare diseases through the application of constrained coding region annotation and de novo status

Genet Med. 2025 Jul;27(7):101447

2-methylbutyryl-CoA dehydrogenase deficiency Usefulness of levels of 2-methylbutyrylglycine and 2-ethylhydracrylic acid in urine for diagnosing 2-methylbutyrylglycinuria

Orphanet J Rare Dis. 2025 Jul 1;20(1):328

Idiopathic achalasia Diagnostic Accuracy of Timed Barium Esophagram for Achalasia

Gastroenterology. 2025 Jul;169(1):63-72

Osteogenesis imperfecta In children under two years of age, does the bone health index value differ between those with and without osteogenesis imperfecta?

Bone. 2025 Jul:196:117467

Pulmonary arterial hypertension Adaptation of ACMG/AMP Guidelines for Clinical Classification of BMPR2 Variants in Pulmonary Arterial Hypertension Resolves Variants of Unclear Pathogenicity in ClinVar

Hum Mutat. 2025 Jul 6:2025:2475635

Systemic lupus erythematosus New IgG and IgA autoantibody specificities against DNA-binding and RNA-binding proteins discriminate systemic lupus erythematosus from health and non-lupus autoimmunity-could anti-LIN28A enhance precision in diagnostics?

Ann Rheum Dis. 2025 Jul;84(7):1180-1194

Thrombotic thrombocytopenic purpura Rapid ADAMTS13 activity assays for thrombotic thrombocytopenic purpura: a systematic review and meta-analysis

Blood. 2025 Jul 10;146(2):233-246

Neonatal Screening

Phenylketonuria: Descriptive analysis of baseline demographic, diagnosis, family history, and genetic testing data from the integrated disease management program for phenylketonuria (IDMP-PKU) (Turkey)

To read more about “Phenylketonuria”

Orphanet J Rare Dis. 2025 Aug 1;20(1):394

Lysosomal storage diseases: Five-year-prospective newborn screening to analyse trends between lysosomal enzyme activities and several demographic variables in Missouri State (United States)

To read more about “Mucopolysaccharidosis type 1”
To read more about “Glycogen storage disease due to acid maltase deficiency”
To read more about “Gaucher disease”
To read more about “Fabry disease”

Int J Neonatal Screen. 2025 Jun 19;11(2):48

Other publications

Please find below some more interesting publications. For a more complete selection, do not hesitate to consult our Newborn Screening Bibliographical Knowledgebase.

Toward the Development of a Novel Newborn Screening Modality: In-Depth Nontargeted Proteome Analysis of Dried Blood Spots with a Robotic Pipeline Using Low-Cost Iron Powders

Anal Chem. 2025 Aug 26;97(33):17992-18000

Adenosine monophosphate deaminase deficiency Seasonal Fluctuations and Stability of Adenosine in Dried Blood Spots for Neonatal Screening

Int J Neonatal Screen. 2025 Aug 13;11(3):63

Allan-Herndon-Dudley syndrome MCT8 Deficiency in Infancy: Opportunities for Early Diagnosis and Screening

Int J Neonatal Screen. 2025 Aug 21; 11(3), 66

Allan-Herndon-Dudley syndrome/

Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta Is It Time to Expand Newborn Screening for Congenital Hypothyroidism to Other Rare Thyroid Diseases?

Int J Neonatal Screen. 2025 Aug 20;11(3):65

Cystic fibrosis Refining CFTR-Related Metabolic Syndrome (CRMS)/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) Diagnosis: Impact of CFTR2 Variant Classifications

Int J Neonatal Screen. 2025 Jul 30;11(3):60

Fabry disease Evaluation of GLA variants detected in newborn screening for Fabry disease using biomarker analysis