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Edition of 28 March 2025

New Syndromes

ARID1A/ARID1B variants cause a distinct and emerging BAFopathy

A new study published in Genetics in Medicine described whole-gene microduplications of ARID1A and ARID1B, which encodes two mutually exclusive proteins with similar structure and function, components of the BAF chromatin remodeling complex responsible for transcriptional activation and repression of select genes. The variants were found among 16 and 13 individuals for ARID1A and ARID1B respectively. Duplications in both of these genes led to shared features, including mild to severe intellectual disability, growth delay, and hand or feet anomalies, occasionally accompanied by a unique facial appearance. Various analyses identified ARID1A or ARID1B microduplications as an additional type of BAFopathy entity, distinct from syndromic intellectual disabitliy or Coffin-Siris syndrome already described in case of haploinsufficiency for these genes.

Genet Med. 2025 Jan;27(1):101283

FLVCR1 variants cause a severe developmental disorder spectrum

A new study published in Genetics in Medicine described biallelic variants in the FLVCR1 gene, coding for a highly conserved choline and ethanolamine transporter, that may play a critical role in erythropoiesis. The variants were found among 30 patients from 23 unrelated families presenting with a broad and pleiotropic phenotypic spectrum ranging from severe developmental disorders, with variable anemia and skeletal malformations, to adult neurodegeneration. Various analyses emphasized the role of FLVCR1 choline and ethanolamine transport into the central and peripheral nervous systems, essential for preventing neurodegeneration and required for normal neurodevelopment.

Genet Med. 2025 Jan;27(1):101273

TSHZ3 variants cause congenital anomalies of the kidney and uriary tract (CAKUT)

A new study published in European Journal of Human Genetics characterized heterozygous missense variants in TSHZ3, which encodes a transcription factor regulating smooth muscle cell differentiation via interaction with SOX9 and myocardin during ureter and kidney development. The variants were found among 12 individuals from 9 unrelated families with CAKUT, in particular multicystic dysplastic kidney, hydronephrosis and proximal hydroureter, as well as speciﬁc extrarenal features such as genital anomalies and cognitive impairement. Various analyses confirmed the role of TSHZ3 in smooth muscle cell differentiation, altered with this gene dysfunction. Futher pathophysiological information revealed that signiﬁcantly altered SOX9 and/or myocardin binding in cases of N-terminal TSHZ3 variants may adversely affect smooth muscle differentiation.

Eur J Hum Genet. 2025 Jan;33(1):44-55

New Genes

Bilateral polymicrogyria: Identification of variants in KIF4A

To read more about “Bilateral polymicrogyria”

Am J Med Genet A. 2025 Jan;197(1):e63860

Charcot-Marie-Tooth disease type 1: Identification of a heterozygous missense variant in ITPR3

To read more about “Charcot-Marie-Tooth disease type 1”

Brain. 2025 Jan 7;148(1):227-237

Kyphomelic dysplasia: Identification of biallelic variants in CCN2

To read more about “Kyphomelic dysplasia”

Eur J Hum Genet. 2025 Jan;33(1):30-37

Non-syndromic genetic deafness: Identification of a heterozygous variant in POLD3

To read more about “Non-syndromic genetic deafness”

Non-specific syndromic intellectual disability: Identification of multiple new variants

Read more (GTF3C3)
Read more (PP2R2B)
Read more (UBR5)

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

Genet Med. 2025 Jan;27(1):101253
Hum Mol Genet. 2025 Jan 29;34(2):193-203
Am J Hum Genet. 2025 Jan 2;112(1):75-86

Oculo-auriculo-vertebral spectrum: Identification of heterozygous variants in CHAF1A

To read more about “Oculo-auriculo-vertebral spectrum”

Eur J Hum Genet. 2025 Jan;33(1):131-136

Perrault syndrome: Identification of biallelic variants in DAP3

To read more about “Perrault syndrome”

Am J Hum Genet. 2025 Jan 2;112(1):59-74

Clinical Research

Facioscapulohumeral dystrophy: Disease course data on childhood onset disease over five years (prospective nationwide cohort, natural history)

To read more about “Facioscapulohumeral dystrophy”

Neurology. 2025 Jan 14;104(1):e210059

TRPV4-related neuromuscular diseases: Demographic and clinical information based on an international registry completed by patient questionnaire (natural history study)

To read more about “Autosomal dominant Charcot-Marie-Tooth disease type 2C”
To read more about “Autosomal dominant congenital benign spinal muscular atrophy”

Brain. 2025 Jan 7;148(1):238-251

Necrotizing enterocolitis: Effectiveness of previously reported methods or tests to identify surgical disease (systematic review and meta-analysis)

To read more about “Necrotizing enterocolitis”

Pediatr Res. 2025 Jan;97(1):45-55

Sickle cell anemia: Safety and efficacy of ketamine use in patients with vaso‐occlusive crisis (systematic review and meta‐analysis)

To read more about “Sickle cell anemia”

EJHaem. 2024 Nov 25;5(6):1312-1321

Moderate/severe hemophilia A: Assessment of burden associated with problem joints in children and adults (cross-sectional studies)

To read more about “Moderate hemophilia A”
To read more about “Severe hemophilia A”

Orphanet J Rare Dis. 2025 Jan 13;20(1):18

Acromegaly: Effective replacement of injected treatment by once-daily oral paltusotine in maintening biochemical and symptom control (phase 3 trial)

To read more about “Acromegaly”

J Clin Endocrinol Metab. 2024 Dec 18;110(1):228-237

Adult hepatocellular carcinoma: Progression-free survival improvement with transarterial chemoembolisation (TACE) plus lenvatinib and pembrolizumab compared with TACE plus placebo (phase 3 trial)

To read more about “Adult hepatocellular carcinoma”

Lancet. 2025 Jan 18;405(10474):203-215

Duchenne muscular dystrophy: Absence of statistical significative efficacy of well-tolerated AAV gene therapy compared to placebo (phase 3 trial)

To read more about “Duchenne muscular dystrophy”

Nat Med. 2025 Jan;31(1):332-341

Hereditary ATTR amyloidosis: Reduction of morbidity and moratlity with vutrisiran compared to placebo among patients with cardiomyopathy (phase 3 trial)

To read more about “Hereditary ATTR amyloidosis”

N Engl J Med. 2025 Jan 2;392(1):33-44

Juvenile idiopathic arthritis: Higher rates of uveitis and/or arthritis relapse by stopping adalimumab, reversed after restarting treatment (phase 4 trial)

To read more about “Juvenile idiopathic arthritis”

Lancet. 2025 Jan 25;405(10475):303-313

Multiple myeloma: No impact of dexamethasone reductions on progression-free and overall survivals during newly diagnosed patients' induction (second analysis of clinical trials)

To read more about “Multiple myeloma”

Blood. 2025 Jan 2;145(1):75-84

Proximal spinal muscular atrophy: Safety profile of IV onasemnogene abeparvovec with maintenance or improvement of motor function among pediatric patients (phase 3b trial)

To read more about “Proximal spinal muscular atrophy”

Neurology. 2025 Jan 28;104(2):e210268

CADASIL: Development of disease staging systems based on clinicoradiological severity and disease progression (international and national cohort study)

Read more (severity spectrum)
Read more (disease progression)

To read more about “Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy (CADASIL)”

JAMA Neurol. 2025 Jan 1;82(1):49-60
Neurology. 2025 Jan 14;104(1):e210193

Huntington disease: Delayed motor onset in premanifest disease and reduced rate of worsening of symptoms in motor manifest disease by β-blocker (observational, longitudinal multicenter study)

To read more about “Huntington disease”

JAMA Neurol. 2025 Jan 1;82(1):85-92

Mucopolysaccharidosis: Cord blood, a viable and expedient option for transplantation to reduce toxicity conditioning (nationwide pediatric cohort, restrospective study)

To read more about “Mucopolysaccharidosis”

EJHaem. 2024 Nov 26;5(6):1295-1300

Therapeutic Approaches

Achondroplasia: Genetic approaches with Fgfr3 enhancer deletion to improve all skeletal features in a mouse model

To read more about “Achondroplasia”

J Clin Invest. 2025 Jan 16;135(2):e184929

Ependymoma: Inhibition of the tumoral growth by dasatinib, a multikinase inhibitor, in both in vitro and in vivo models

To read more about “Ependymoma”

Proc Natl Acad Sci U S A. 2025 Jan 28;122(4):e2319474122

GATA6-associated hepatic diseases: Establishment of a knockout zebrafish provides insights into both disease phenotypes and mechanisms in patients

To read more about “Isolated agenesis of gallbladder”
To read more about “Pancreatic hypoplasia-diabetes-congenital heart disease syndrome”
To read more about “Tetralogy of Fallot”

Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2317801121

Malignant peripheral nerve sheath tumor: Durable responses by combining SHP2 inhibition with hydroxychloroquine both in genetic and orthotopic xenograft mouse models

To read more about “Malignant peripheral nerve sheath tumor”

Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2407745121

Multiple myeloma: Efficacy of forimtamig, a novel GPRC5D-targeting T-cell bispeciﬁc antibody, in a mouse model

To read more about “Multiple myeloma”

Blood. 2025 Jan 9;145(2):202-219

Non-Hodgkin lymphoma: Effective dual-targeting approaches with co-transduction of CD19 and BCMA CAR-T therapy both in vitro and in vivo

To read more about “Non-Hodgkin lymphoma”

Mol Ther. 2025 Jan 8;33(1):317-335

Pompe disease: Restoration of glycogen balance with a novel siRNA conjugate targeting CD71 and GYS1 in a mouse model

To read more about “Glycogen storage disease due to acid maltase deficiency (Pompe disease)”

Mol Ther. 2025 Jan 8;33(1):235-248

X-linked sideroblastic anemia: Improvement of anemia and iron metabolism by an erythroid-specific lentiviral vector in a new mouse model

To read more about “X-linked sideroblastic anemia”

Blood. 2025 Jan 2;145(1):98-113

Biomarkers

AL amyloidosis: Pulmonary artery wedge pressure/cardiac index ratio as a significant prognostic marker in patients with stage IIIb cardiac form

To read more about “AL amyloidosis”

Orphanet J Rare Dis. 2025 Jan 13;20(1):19

Behçet disease: Characteristic plasma metabolic profiles in intestinal forms using an untargeted LC/MS metabolomics profiling approach

To read more about “Behçet disease”

Orphanet J Rare Dis. 2025 Jan 13;20(1):21

Cerebral Amyloid Angiopathy: Cerebral microenhancement as a imaging biomarker in detecting blood-brain barrier rupture preceding cerebral microbleed development in inflammatory variants

To read more about “Cerebral Amyloid Angiopathy”

Neurology. 2025 Jan 28;104(2):e210258

Fibrodysplasia ossificans progressiva: Comparison of two imaging modalities for the detection and volumetric measurement of heterotopic ossifications

To read more about “Fibrodysplasia ossificans progressiva”

Bone. 2025 Jan:190:117280

Gaucher disease: Evaluation of glucosylsphingosine as a biomarker for disease treatment outcomes

To read more about “Gaucher disease”

Orphanet J Rare Dis. 2025 Jan 29;20(1):43

Multiple myeloma: Soluble B-cell maturation antigen as biomarker in monitoring oligosecretory/nonsecretory forms and for early relapse detection and prediction

To read more about “Multiple myeloma”

Blood. 2025 Jan 30;145(5):526-532

Neuroendocrine tumor of pancreas: Risk stratification of the metastatic phenotype using machine learning based on primary tumoral transcriptomic signature

To read more about “Neuroendocrine tumor of pancreas”

J Clin Endocrinol Metab. 2024 Dec 18;110(1):263-274

Spinocerebellar ataxia type 3: Expanded CAG repeat size, associated with volume loss in the cerebellum and cervical cord, and motor function, as a biomarker for disease progression and assessing therapeutic efficacy

To read more about “Spinocerebellar ataxia type 3”

Orphanet J Rare Dis. 2025 Jan 23;20(1):35

Systemic sclerosis: Epitope spreading of anti‐RNA polymerase III antibodies as potential biomarker for skin and lung involvement

To read more about “Systemic sclerosis”

Arthritis Rheumatol. 2025 Jan;77(1):67-79

Diagnostic Approaches

Autoimmune encephalitis: Differential diagnosis and comparison of diagnostic algorithms in children and adolescents

To read more about “Autoimmune encephalitis”

Lancet Neurol. 2025 Jan;24(1):54-64

Late-onset Pompe disease: Identification of at-risk patients using a multipart symptom-specific-based scoring tool

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

Orphanet J Rare Dis. 2025 Jan 14;20(1):23

Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia: Innovative diagnostic approach using machine learning model based on plasma acylcarnitine profiles

To read more about “Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia”

Orphanet J Rare Dis. 2025 Jan 9;20(1):15

Mitochondrial disease: National study providing ultrarapid molecular diagnosis to critically ill infants and children with suspected disease

To read more about “Mitochondrial disease”

Genet Med. 2025 Jan;27(1):101293

Non-acquired isolated growth hormone deficiency: Evaluation of threshold values for glucagon test in the disease definition during the transition age

To read more about “Non-acquired isolated growth hormone deficiency”

J Clin Endocrinol Metab. 2024 Dec 18;110(1):78-90

Non-syndromic genetic deafness: Novel advanced noninvasive prenatal diagnosis assay for singleton and twin pregnancies in the first trimester

To read more about “Non-syndromic genetic deafness”

Orphanet J Rare Dis. 2025 Jan 27;20(1):40

Ornithine transcarbamylase (OTC) deficiency: Simple and stable approach for applying OTC activity testing using neonatal heel-prick blood samples

To read more about “Ornithine transcarbamylase deficiency”

Orphanet J Rare Dis. 2025 Jan 8;20(1):9

Primary ciliary dyskinesia: Standardized method to identify pathogenic variants using airway epithelium transcriptome analysis

To read more about “Primary ciliary dyskinesia”

Hum Mol Genet. 2025 Jan 29;34(2):148-160

Retinitis pigmentosa: Validation and integration of Nanopore long-read ORF15 sequencing in a routine molecular laboratory

To read more about “Retinitis pigmentosa”

Eur J Hum Genet. 2025 Jan;33(1):80-88

Neonatal Screening

Inborn errors of immunity/Wilson disease: Effectiveness and feasability of using high-throughput LC-MS/MS assay for NBS in Washington State (USA)

To read more about “Adenosine monophosphate deaminase deficiency”
To read more about “Wilson disease”
To read more about “Wiskott-Aldrich syndrome”
To read more about “X-linked agammaglobulinemia”

Int J Neonatal Screen. 2025 Jan 10;11(1):6

Lysosomal storage diseases: First year-outcomes of a pilot NBS project using digital microfluidic technique in Campania region (Italy)

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

Mol Genet Metab. 2025 Feb;144(2):109008

Neonatal intrahepatic cholestasis due to citrin deficiency: Sensitivity and specificity improvement for detecting missed cases in China by combining multiple metabolic markers (amino acids and acylcarnitines)

To read more about “Neonatal intrahepatic cholestasis due to citrin deficiency”

Orphanet J Rare Dis. 2025 Jan 11;20(1):17

Primary Hyperoxaluria type 1 or 3: Efficacy of a genomic NBS program in Germany

To read more about “Primary hyperoxaluria type 1”
To read more about “Primary hyperoxaluria type 3”

Kidney Int Rep. 2024 Oct 12;10(1):177-183

Proximal spinal muscular atrophy: Outcomes of a pilot NBS program based on genetic testing in Valencian Community (Spain)

To read more about “Proximal spinal muscular atrophy”

Int J Neonatal Screen. 2025 Jan 14;11(1):7

Rare inborn errors of metabolism: Identification of diseases eligible for DNA-first NBS based on treatibility in the Netherlands

To read more about “Rare inborn errors of metabolism”

Int J Neonatal Screen. 2024 Dec 28;11(1):1

Rare inborn errors of metabolism: Validation of a workflow-based combined biochemical profiling and DNA sequencing analyses NBS in Campania region (Italy)

To read more about “Rare inborn errors of metabolism”

Orphanet J Rare Dis. 2025 Jan 24;20(1):38

Interim results of acceptability, feasibility, and outcomes of an ongoing genomic NBS study in a diverse population in New York City (USA)

JAMA. 2025 Jan 21;333(3):232-240

Patient Management and Therapy

Acute lymphoblastic leukemia: Discussion focused on improvement of risk stratiﬁcation and incorporation of novel strategies to reduce relapse rate and current treatment toxicity in infants

To read more about “Acute lymphoblastic leukemia”

Blood. 2025 Jan 2;145(1):35-42

Amyotrophic lateral sclerosis: Pathological mechanisms to support future therapy development, from genetic discovery to disease prevention

Read more (Therapeutic strategy)
Read more (Predictive genetic testing)
Read more (SOD1 variants)

To read more about “Amyotrophic lateral sclerosis”

Ann Neurol. 2024 Nov 6;97(1):15-27
Eur J Hum Genet. 2025 Jan;33(1):7-13
Lancet Neurol. 2025 Jan;24(1):77-86

B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2): Clinical cases to discuss oppportunities and challenges in the disease management

Read more (Adult)
Read more (Children, adolescents, young adults)

To read more about “B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)”

Blood. 2025 Jan 2;145(1):11-19
Blood . 2025 Jan 2;145(1):20-34

Combined immunodeficiency due to FCHO1 deficiency: Comprehensive systematic review on molecular genetics, clinical manifestations, disease pathogenesis and potential therapeutic targets

To read more about “Combined immunodeficiency due to FCHO1 deficiency”

Am J Med Genet A. 2025 Jan;197(1):e63855

Diffuse large B-cell lymphoma: Management of older patients with relapsed/refractory disease

To read more about “Diffuse large B-cell lymphoma”

Blood. 2025 Jan 16;145(3):277-289

Follicular lymphoma: Review on the therapeutic role of chimeric antigen receptor T cells and bispecific antibodies

To read more about “Follicular lymphoma”

Blood. 2025 Jan 9;145(2):170-175

Hematologic disorders: Overview of iron overload management based on iron biology informs

Read more (Hemoglobinopathy)
Read more (Myelodysplastic syndrome)

To read more about “Hemoglobinopathy”
To read more about “Myelodysplastic syndrome”

Blood. 2025 Jan 23;145(4):359-371
Blood . 2025 Jan 23;145(4):383-396

Neuroendocrine neoplasm: Classification and management of major lung subtypes based on clinical, pathological, molecular, and genomic profiles

To read more about “Neuroendocrine neoplasm”

Lancet Oncol. 2025 Jan;26(1):e13-e33

Precursor T-cell acute lymphoblastic leukemia: Questions about current and novel approaches for pediactric, adolescent and young adult patients

To read more about “Precursor T-cell acute lymphoblastic leukemia”

Blood. 2025 Jan 2;145(1):43-52

SAMD9 and SAMD9L syndromes: Clinical spectrum, variant interpretation, clinical management and surveillance

To read more about “Ataxia-pancytopenia syndrome”
To read more about “MIRAGE syndrome”
To read more about “SAMD9L-associated autoinflammatory syndrome”
To read more about “Spinocerebellar ataxia type 49”

Blood. 2025 Jan 30;145(5):475-485

Recommendations

Germline pathogenic ATM variant-related cancers: Clinical practice resource to guide disease management (from American College of Mecical Genetics and Genomics)

To read more about “Familial prostate cancer”
To read more about “Hereditary breast cancer”

Genet Med. 2025 Jan;27(1):101243

Lysosomal diseases: Technical standard for biomarker analysis, result interpretation, and result reporting (from American College of Medical Genetics and Genomics)

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

Genet Med. 2025 Jan;27(1):101242

Maple syrup urine disease: Comprehensive guidelines for diagnosis and management (Iranian evidence- and consensus- based approach)

To read more about “Maple syrup urine disease”

Orphanet J Rare Dis. 2025 Jan 7;20(1):8

Multiple myeloma: Consensus statements to support the effective introduction of novel treatments for relapsed or refractory disease in the UK National Health Service

To read more about “Multiple myeloma”

EJHaem. 2024 Oct 25;5(6):1133-1143

Phenylketonuria: Clinical practice guideline for diagnosis and management (based on 2023 American College of Medical Genteics and Genomics systematic review)

To read more about “Phenylketonuria”

Genet Med. 2025 Jan;27(1):101289

Rare arteriovenous malformation: Diagnosis and management of superficial forms (French healthcare network’s recommendations)

To read more about “Rare arteriovenous malformation”

Orphanet J Rare Dis. 2025 Jan 30;20(1):45

Sturge-Weber syndrome: Multidisciplinary expert consensus for diagnosis, treatment, and follow-up of all disease manifestations (Italian Law on Rare Disease Care's recommendations)

To read more about “Sturge-Weber syndrome”

Orphanet J Rare Dis. 2025 Jan 16;20(1):28

Systemic sclerosis: International collaborative systematic literature review informing the 2023 EULAR recommendations for the treatment

To read more about “Systemic sclerosis”

Ann Rheum Dis. 2025 Jan;84(1):29-40

Epidemiology

Enteropathy-associated T-cell lymphoma: Nationwide population-based registry cohort study on incidence, treatment, and outcome in the Netherlands

To read more about “Enteropathy-associated T-cell lymphoma”

EJHaem. 2024 Nov 29;5(6):1215-1222

Epilepsy syndrome: Estimation of real-world evidence-based prevalence rate of genetic developmental and epileptic encephalopathies in Italy over a 11-year period

To read more about “Epilepsy syndrome”

J Med Genet. 2024 Dec 31;62(1):25-31

Hereditary ATTR amyloidosis: Summary of current data on the epidemiology and mortality rates

To read more about “Hereditary ATTR amyloidosis”

Orphanet J Rare Dis. 2025 Jan 16;20(1):29

Myasthenia gravis: Changes in myasthenia gravis incidence in Denmark from 1985 to 2021

To read more about “Myasthenia gravis”

Neurology. 2025 Jan 14;104(1):e210139

Functional Impact

B-cell chronic lymphocytic leukemia: Establishment of meaningful change thresholds to guide the interpretation of EORTC QLQ-CLL17 domain scores in adults with relapsed or refractory disease

To read more about “B-cell chronic lymphocytic leukemia”

EJHaem. 2024 Oct 7;5(6):1165-1172

Hereditary angioedema: Qualitative study of disease experience and health-related quality of life among adolescents

To read more about “Hereditary angioedema”

Orphanet J Rare Dis. 2025 Jan 10;20(1):16

Inherited epidermolysis bullosa: Physical, emotional, social, and functional dimensions and helpful aspects from a patients’ perspective

To read more about “Inherited epidermolysis bullosa”

Orphanet J Rare Dis. 2025 Jan 6;20(1):3

Myasthenia gravis: Validation of a novel disease-specific patient-reported outcome measure for ocular form

To read more about “Myasthenia gravis”

Neurology. 2025 Jan 14;104(1):e210150

Syndromic heritable thoracic aortic diseases: Qualitative study to investigate the perceptions and opinions of important determinants for quality of life in patients

To read more about “Loeys-Dietz syndrome”
To read more about “Marfan syndrome”
To read more about “Vascular Ehlers-Danlos syndrome”

Orphanet J Rare Dis. 2025 Jan 9;20(1):12

Summary of the edition of 28 March 2025

Editorial
- Editorial
- ERN News
Political news
Scientific news
And also...