Prevedello F, Ali DS, Piccolo C
… +8 more, Rigon C, Forzan M, Tacchetto E, Palmitessa R, Calosci D, Salviati L, Gurrieri C, Trevisson E
Am J Med Genet A
· 2026 Aug · PMID 41866794
·
Publisher ↗
Noonan syndrome (NS) is a genetically heterogeneous disorder characterized by a broad spectrum of clinical features resulting from dysregulation of the RAS/MAPK pathway. Although complex genotypes are increasingly recogn...Noonan syndrome (NS) is a genetically heterogeneous disorder characterized by a broad spectrum of clinical features resulting from dysregulation of the RAS/MAPK pathway. Although complex genotypes are increasingly recognized in NS, cases harboring two distinct pathogenic variants in different NS genes remain extremely rare. We describe the case of a 53-year-old female presenting a severe NS phenotype-including short stature, facial dysmorphism, congenital heart defect, and developmental delay-and concurrent acute myeloid leukemia (AML). Targeted NGS analysis of a RASopathy-specific gene panel identified a constitutional heterozygous PTPN11 variant (c.1472C>T, p.(Pro491Leu)) and a mosaic RIT1 variant (c.229G>C, p.(Ala77Pro), 16.45% VAF), both meeting criteria for pathogenicity. The RIT1 variant was validated via PCR-RFLP across multiple tissues, excluding leukemia-driven clonal expansion, and further quantified by high-depth amplicon-based sequencing. To our knowledge, this case represents a unique example of NS associated with pathogenic variants in two distinct RASopathy genes. Our findings underscore that comprehensive molecular characterization and multi-tissue validation are essential for accurate diagnosis, genetic counseling, and personalized management, while also revealing that combinatorial RAS/MAPK alterations may influence disease severity and clinical outcomes.
Thakral A, Santoli CMA, Idowu O
… +7 more, Dowd C, Vassar RL, Devine WP, Van Ziffle J, Frieden IJ, Tam A, Shieh JT
Am J Med Genet A
· 2026 Aug · PMID 41856681
·
Publisher ↗
Encephalocraniocutaneous lipomatosis (ECCL) is a neurocutaneous condition caused by postzygotic mosaic activating variants in genes including FGFR1, NRAS, or KRAS. It primarily affects the skin, eyes, and central nervous...Encephalocraniocutaneous lipomatosis (ECCL) is a neurocutaneous condition caused by postzygotic mosaic activating variants in genes including FGFR1, NRAS, or KRAS. It primarily affects the skin, eyes, and central nervous system. Diagnosis is typically based on characteristic clinical features and/or molecular confirmation. Here we report a unique case of ECCL in a 12-year-old female with abdominal wall lipoma, ipsilateral lower limb overgrowth, and brachydactyly, in whom somatic mosaicism for FGFR1 was identified using resected lipomatous tissue. Imaging studies confirmed additional spinal lipomas consistent with ECCL. This report expands the phenotypic spectrum of FGFR1-ECCL and underscores the importance of tissue-based somatic testing for diagnosis. Tumor risk is also discussed.
Mohr J, Frederiksen AL, Duno M
… +3 more, Hermann AP, Juul TM, Nielsen SR
Am J Med Genet A
· 2026 Aug · PMID 41856674
·
Publisher ↗
Mitochondria are essential intracellular organelles that play a critical role in cellular metabolism, including the regulation of intracellular calcium signaling. Advances in genomic sequencing have facilitated the ident...Mitochondria are essential intracellular organelles that play a critical role in cellular metabolism, including the regulation of intracellular calcium signaling. Advances in genomic sequencing have facilitated the identification of rare pathogenic mitochondrial DNA (mtDNA) genetic variants in patients with unexplained endocrine disorders. We present a case report of a woman diagnosed with the rare mtDNA variant m.10010T>C. The case report includes a detailed clinical evaluation, heteroplasmy measurements across several tissues, and a review of previously published cases of patients heteroplasmic for the m.10010T>C variant. The patient developed myopathy and exercise-induced dyspnoea at 24 years of age. Nineteen years later, progressive muscle symptoms were accompanied by elevated blood lactate and hypoparathyroidism. Muscle biopsy revealed abnormal mitochondrial morphology with cytochrome C oxidase-negative fibers and deficiencies in respiratory chain Complexes I, II, and IV. Genetic analysis identified the m.10010T>C variant with 95% heteroplasmy in the muscle biopsy, 20% in urine, 4% in buccal mucosa, and undetectable in blood (< 1%). We report the first case of a m.10010T>C carrier with hypoparathyroidism, which is a rare and unexplained finding in mitochondrial disorders that may exacerbate myopathy.
Papingi D, Kutsche M, Lichtenfeld H
… +4 more, Kortüm F, Abicht A, Herrmann L, Herget T
Am J Med Genet A
· 2026 Aug · PMID 41851022
·
Publisher ↗
Griscelli Syndrome Type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic mutations in the RAB27A gene. Typically, it is characterized by cutaneous hypopigmentation, immunodeficiency, with or without ne...Griscelli Syndrome Type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic mutations in the RAB27A gene. Typically, it is characterized by cutaneous hypopigmentation, immunodeficiency, with or without neurological abnormalities secondary to hemophagocytic lymphohistiocytosis (HLH). Without treatment, GS2 often results in fatal outcomes within the first decade of life. Adult-onset GS2 is extremely rare, with few documented cases. We describe a 48-year-old patient with a neurological presentation: cerebellar dysarthria, ataxia, nystagmus, and muscle hypotonia in the lower limbs. Diagnostic workup included next-generation sequencing (NGS panel), clinical investigations, and segregation analysis in the family to confirm the diagnosis of GS2. Genetic testing revealed two variants in RAB27A: The likely pathogenic c.550C>T [p.(Arg184*)] and c.213G>T [p.(Gln71His)], a variant of uncertain significance. Clinical evaluation confirmed irregular hair pigmentation due to melanosome transport defect, low natural killer cell activity, cytopenia, hypertriglyceridemia, elevated serum ferritin, and brain tissue biopsy compatible with hemophagocytosis, thus cementing the clinical diagnosis of GS2. Segregation analysis confirmed the trans configuration of the variants. Based on the clinical and genetic evidence, the p.Gln71His variant was reclassified as likely pathogenic per ACMG criteria. This rare late-onset GS2 case highlights the need to consider GS2 in adult patients with atypical presentations. Early diagnosis is vital for effective intervention. Greater clinical awareness and research are needed to understand its phenotypic spectrum in adults.
Am J Med Genet A
· 2026 Aug · PMID 41845542
·
Publisher ↗
People with Phelan-McDermid syndrome (PMS) have reduced speech and language abilities, yet little research has profiled the communication abilities in this population. The purpose of this study was threefold: identifying...People with Phelan-McDermid syndrome (PMS) have reduced speech and language abilities, yet little research has profiled the communication abilities in this population. The purpose of this study was threefold: identifying the language and communication profiles of school-aged children with PMS, identifying genetic contributions to language and communication abilities, and determining the feasibility of remote data collection for research purposes. A speech language pathologist used standardized assessments and direct evaluations by video conferencing to evaluate language and communication abilities. Sixteen children and adolescents were evaluated: 5 with SHANK3 pathogenic variants, 9 with 22q13 deletions including SHANK3 (PMS-SHANK3 related), and 2 with 22q13 deletions preserving SHANK3 (PMS-SHANK3 unrelated). All showed moderate-to-severe language impairment across all assessments. Females demonstrated higher communication abilities than males. Haploinsufficiency of SHANK3 appears to be the main driver of language impairment in PMS; however, participants with preserved SHANK3 also scored in the impairment range, suggesting other contributions from 22q13 genes to the language phenotype. This study demonstrates the efficacy of using standardized instruments and remote data collection methods to assess communication in PMS. Remote methods may be helpful for the assessment of other genetic disorders involving language phenotypes.
Kothari N, Shannon N, Erhayiem B
… +4 more, Suri M, Yu J, Pagnamenta AT, Dixit A
Am J Med Genet A
· 2026 Aug · PMID 41844566
·
Publisher ↗
Characterization of the molecular basis of connective tissue disorders causing aortopathy is important for clinical management. We report a 4-generation family with autosomal dominant inheritance of a connective tissue d...Characterization of the molecular basis of connective tissue disorders causing aortopathy is important for clinical management. We report a 4-generation family with autosomal dominant inheritance of a connective tissue disorder causing aortic dilatation and/or dissection. Linkage analysis performed in the 1990s had suggested Marfan syndrome, but the molecular basis proved elusive over two decades. Reanalysis of genome sequence data using software to detect copy number variation (CNV) identified a 19 kb deletion including the final exon of TGFB2, revealing Loeys-Dietz syndrome type 4 as the actual diagnosis. This allowed predictive testing of at-risk relatives and appropriate screening of affected patients. Small genomic deletions are difficult to detect on microarray and standard sequencing platforms, and the report highlights the role of high-resolution CNV detection in molecular diagnostics.
Am J Med Genet A
· 2026 Aug · PMID 41844548
·
Publisher ↗
Noninvasive prenatal cell-free DNA (cfDNA) screening is standard of care for detecting prenatal chromosomal aneuploidies. The positive predictive value of prenatal cfDNA screening is lower for sex chromosome aneuploidies...Noninvasive prenatal cell-free DNA (cfDNA) screening is standard of care for detecting prenatal chromosomal aneuploidies. The positive predictive value of prenatal cfDNA screening is lower for sex chromosome aneuploidies (SCAs) compared to autosomal aneuploidies due to sex chromosome mosaicism and the potential for subclinical maternal sex chromosome aneuploidy. In some cases, these factors can result in indeterminate cfDNA results for SCAs. We present three cases which highlight higher-copy sex chromosome aneuploidies (HC SCAs; i.e., tetrasomy and pentasomy for the sex chromosomes) as one cause of an indeterminate sex chromosome prenatal cfDNA result. Timely diagnosis of HC SCAs enables informed pregnancy management and decision-making. Thus, these cases underscore the potential value of an indeterminate result by cfDNA screening and the importance of comprehensive genetic counseling and follow-up diagnostic testing when faced with indeterminate cfDNA results, particularly regarding the risk of HC SCAs.
Malik I, Banday AZ, Bhat AS
… +5 more, Jan UM, Reshie AA, Fayaz F, Basharat S, Wani NA
Am J Med Genet A
· 2026 Aug · PMID 41839820
·
Publisher ↗
Only a few studies describe five (or more) patients with inherited glycerol-3-phosphate dehydrogenase 1 (GPD1) deficiency, often termed transient infantile hypertriglyceridemia (HTGTI). We report 18 additional patients w...Only a few studies describe five (or more) patients with inherited glycerol-3-phosphate dehydrogenase 1 (GPD1) deficiency, often termed transient infantile hypertriglyceridemia (HTGTI). We report 18 additional patients with HTGTI (confirmed molecular diagnosis in 16, a variant of uncertain significance in two), most of whom presented in infancy with hepatomegaly. A significant negative correlation was noted between age at presentation and serum triglyceride levels. Except for two, all our patients have homozygous GPD1 variants, wherein the c.500G>A (p.Gly167Asp) variant was the most common (10 patients). Other variants identified included c.220-1G>T, c.398C>T (p.Ser133Leu, unpublished), c.806G>A (p.Arg269Gln), and c.685C>T (p.Arg229Trp, novel). Homozygosity matching in patients with the biallelic c.500G>A variant showed that the GPD1 gene is located within the only shared region of homozygosity (> 1 Mb). These patients also have a similar homozygous haplotype around the variant, construing its founder effect in South Asian patients with inherited GPD1 deficiency. Targeted testing for c.500G>A could be considered as a first-tier evaluation strategy in South Asian patients with HTGTI. However, given our limited sample size, further validatory studies are needed.
Castel P, Schoyer L, Stronach B
… +39 more, Bogdanova R, Bennett AM, Blakeley J, Bornhorst M, Bowers T, Brachmann SM, Burkitt-Wright E, Chatfield K, De Luca A, El-Chammas K, Elkadri A, Fortunato JE, Gelb BD, Goriely A, Gripp K, Grover K, Homan L, Kern KA, Kiuru M, Lawson CC, Lee YS, McCormick F, Ney G, Nuevo-Tapioles C, Pardej S, Pierpont EI, Plank J, Ratner N, Rauen KA, Robinson JE, Rogers L, Sheppard SE, Shiels K, Stevenson D, Tiemens D, Traylor M, Weaver KN, Yohe M, Green T
Am J Med Genet A
· 2026 Aug · PMID 41834696
·
Publisher ↗
The RASopathies are a group of congenital disorders with overlapping clinical manifestations that are caused by pathogenic germline or early somatic variants that result in the hyperactivation of the RAS/mitogen-activate...The RASopathies are a group of congenital disorders with overlapping clinical manifestations that are caused by pathogenic germline or early somatic variants that result in the hyperactivation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. Given the heterogeneous clinical presentations of these disorders that involve abnormalities across multiple organ systems, multidisciplinary clinical management and progress in scientific research are essential for optimal patient diagnosis and care. The 9th International RASopathies Symposium, a biennial meeting, was organized by the patient advocacy group RASopathies Network and showcased recent discoveries, case studies, and advances in preclinical research. Participants, who included scientists, clinicians, industry representatives, patients, and family advocates, explored knowledge gaps, innovative clinical approaches, and lived experiences of individuals with a RASopathy. Sessions centered around organ systems were introduced with a patient perspective to highlight the burden of disease, continued with presentations from established and early-career investigators. Overall, the RASopathies Symposia serve as a catalyst for sustained community collaboration focused on enhancing patient health and accelerating the translation of discoveries into effective treatments.
Rashidi K, Modi BP, Richmond PA
… +9 more, Mangino M, Byres L, McDonald C, Dalmann J, Samra S, Bel KLD, Lehman A, Zambonin JL, Turvey SE
Am J Med Genet A
· 2026 Jul · PMID 41826279
·
Publisher ↗
Carpenter syndrome type 2 (CRPT2) is a rare autosomal recessive disease mainly characterized by craniosynostosis and polysyndactyly. CRPT2 is the rarer subtype of Carpenter syndrome (CRPTS) and is caused by biallelic var...Carpenter syndrome type 2 (CRPT2) is a rare autosomal recessive disease mainly characterized by craniosynostosis and polysyndactyly. CRPT2 is the rarer subtype of Carpenter syndrome (CRPTS) and is caused by biallelic variants in the multiple epidermal growth factor-like domains 8 gene (MEGF8). Due to its rarity and phenotypic overlap with other craniosynostosis syndromes, definitive molecular diagnosis of CRPT2 can be challenging. Here, we describe a proband with CRPT2 carrying compound heterozygous variants in MEGF8: one de novo variant disrupting splicing and a maternally inherited missense variant. To resolve these variants, we leveraged long-read genome sequencing to phase the missense variant alleles and RNA sequencing to determine splicing impact. This case highlights the diagnostic value of using sequencing methods beyond the more conventional short-read exome sequencing. Our findings expand the spectrum of MEGF8 variants causing CRPT2 and underscore the utility of emerging sequencing technologies in elucidating complex or previously unresolved genotypes. Expanding access to such technologies is anticipated to accelerate rare disease diagnosis and deepen our understanding of the genetic mechanisms underlying these conditions.
Warmoeskerken T, Theunis M, Van den Bogaert K
… +2 more, Devriendt K, Breckpot J
Am J Med Genet A
· 2026 Jul · PMID 41821414
·
Publisher ↗
The rare X-linked female-restricted Hardikar syndrome (HDKR, OMIM # 301068) is characterized by multiple congenital anomalies including orofacial clefts, gastrointestinal, genitourinary, and cardiac anomalies, but cognit...The rare X-linked female-restricted Hardikar syndrome (HDKR, OMIM # 301068) is characterized by multiple congenital anomalies including orofacial clefts, gastrointestinal, genitourinary, and cardiac anomalies, but cognitive and neurobehavioral development is rarely impaired. HDKR is caused by heterozygous frameshift, splice or nonsense variants in the MED12 gene. Besides HDKR, MED12 pathogenic variants cause a broad spectrum of developmental disorders, collectively referred to as MED12-related disorders, including Opitz-Kaveggia syndrome or FG syndrome type 1 (OKS, OMIM #305450), Lujan-Fryns syndrome (MRXSLF, OMIM #309520), X-linked Ohdo syndrome (OHDOX, OMIM #300895) and isolated intellectual disability. Here we report four individuals with HDKR, including the first of maternally inherited HDKR, and we review molecular and clinical data from 33 individuals with HDKR and 215 individuals with other MED12-related disorders retrieved through a literature and public database search. We highlight sella turcica cysts as a new Hardikar syndrome-related feature, and we introduce clinical guidelines for the diagnosis and management of individuals with HDKR.
Abu-El-Haija A, Bayat A, Mancılar H
… +16 more, Uctepe E, Esen FN, Tumer S, Metli K, Yesilyurt A, Jamra RA, Lalani S, Levy R, Mihalek I, Redler S, Mullegama SV, Umair M, Wegler M, Nawaz S, Yang E, Bodamer O
Am J Med Genet A
· 2026 Jul · PMID 41821366
·
Publisher ↗
The embryonic development of the cerebellum is orchestrated through a dynamic process that governs the interplay of Purkinje and granule cell populations. SKOR2 (Fussel 18) is a transcriptional co-repressor that increase...The embryonic development of the cerebellum is orchestrated through a dynamic process that governs the interplay of Purkinje and granule cell populations. SKOR2 (Fussel 18) is a transcriptional co-repressor that increases SHH (sonic hedgehog) expression which is a potent signal for granule cell proliferation and integration into the complex neuronal network that underlies cerebellar function and development. Complete loss of Skor2 function in a murine model has been shown to result in cerebellar hypoplasia due to severe disruption of the cerebellar vermis. Through GeneMatcher we identified eight individuals from five unrelated families with compound heterozygous or homozygous loss of function, splice site and missense variants in SKOR2 associated with a phenotypic spectrum of cerebellar hypoplasia, microcephaly, ataxia, developmental delays and intellectual disability. Variants identified in SKOR2 included homozygous c.1877delC; p.Pro626Glnfsx156 in the first individual, homozygous c.2752 + 1G>T in the second and third individuals, compound heterozygous c.757T>G p.C253G, c.949T>A p.S317T in the fourth individual, homozygous c.421_424del (p.Asp141Ilefs*118) in the fifth, sixth, and seventh individuals, and a homozygous c.1169C>A; p.Ser390* in the eighth individual. The eight individuals had various degrees of developmental and speech delays, as well as cerebellar hypoplasia identified in some of them. In silico analysis supported pathogenicity of most of SKOR2 variants, except for case 4, and their impact on protein function. Recently, SKOR2 is reported to be associated with Valence-Farazi Cerebellar Ataxia Syndrome (OMIM # 621386) (Skor2-OMIM-OMIM.ORG). This study expands the phenotypic spectrum for this newly described condition. Additional studies in affected individuals will be needed to refine the phenotypic spectrum and identify genotype-phenotype correlations.
Gossios TD, Ntelios D, Zegkos T
… +7 more, Parcharidou D, Rouskas P, Katranas S, Papoulidis I, Ninios V, Ziakas A, Efthimiadis GK
Am J Med Genet A
· 2026 Jul · PMID 41813625
·
Publisher ↗
The key diagnostic criterion for hypertrophic cardiomyopathy is the presence of otherwise unexplained hypertrophy. Current definitions of HCM rely on specific thresholds to establish a diagnosis, while guideline directed...The key diagnostic criterion for hypertrophic cardiomyopathy is the presence of otherwise unexplained hypertrophy. Current definitions of HCM rely on specific thresholds to establish a diagnosis, while guideline directed risk stratification algorithms take its magnitude into consideration. Presently, secondary features such as myocardial crypts and valve abnormalities in the absence of hypertrophy are solely considered as markers of preclinical disease in variant carriers, with no perceptible excess risk for arrhythmic events. Strictly adhering to hypertrophy as the sole criterion for a diagnosis may at times result in delays in diagnosis of the condition in the proband and consequently initiation of family screening. At the same time, arrhythmic risk in individuals with minimal or no hypertrophy may be underestimated. In this study, we describe a novel ACTC1 variant expressed with arrhythmic instability in the proband, closely segregating in family members. The presenting phenotype is characterized by frank secondary abnormalities related to HCM in the absence of conventional wall thickness criteria to establish a formal diagnosis. Thereby, the description of this phenotype may challenge the established perception that hypertrophy is a prerequisite for establishing an HCM diagnosis.
O'Neill A, Bayer C, McQuillen E
… +3 more, Smith ED, Towne M, Reed D
Am J Med Genet A
· 2026 Jul · PMID 41813616
·
Publisher ↗
GCNT2-related cataracts is a disorder characterized by bilateral congenital cataracts (CC) of various types (with or without the adult i blood phenotype) and is caused by biallelic variants in GCNT2, which has 3 major is...GCNT2-related cataracts is a disorder characterized by bilateral congenital cataracts (CC) of various types (with or without the adult i blood phenotype) and is caused by biallelic variants in GCNT2, which has 3 major isoforms, differentiated by alternative splicing of the first exon (known as exon 1A, B, and C). While the transcript that includes exon 1C is thought to be key for the adult i blood phenotype, it is not clear which transcript(s) are clinically relevant for the CC disease phenotype. We report a proband with CC and a truncating variant in exon 1B (NM_001491.3: c.760dup p.H254Pfs*2) found in trans with a 75 kilobase (kb) copy-number deletion encompassing exon 1B and 1C. To our knowledge, c.760dup is the first reported disease-associated variant limited to exon 1B of GCNT2. This report strongly suggests that NM_001491.3, which includes exon 1B, is a clinically relevant transcript for GCNT2-related cataracts and adds to the variant spectrum for this understudied gene-disease relationship. This finding has implications for genotype-phenotype correlations of GCNT2 related CC and variant classification, particularly for truncations in exon 1B, which should likely receive strong pro-pathogenic weight based on this being a clinically relevant exon.
Bobbio E, Caiazza M, Monda E
… +14 more, Aruta G, Budillon A, Esposito A, Fusco A, Cirillo A, Rubino M, Viscovo I, Scarano G, Monica MD, Nigro V, Piluso G, Pecchia L, Russo MG, Limongelli G
Am J Med Genet A
· 2026 Jul · PMID 41813603
·
Publisher ↗
RASopathies are a group of genetic disorders caused by pathogenic variants in the RAS-mitogen-activated protein kinase (RAS-MAPK) signaling pathway, often presenting with congenital heart defects, craniofacial dysmorphis...RASopathies are a group of genetic disorders caused by pathogenic variants in the RAS-mitogen-activated protein kinase (RAS-MAPK) signaling pathway, often presenting with congenital heart defects, craniofacial dysmorphisms, and developmental delays. To assess the diagnostic yield of genetic testing in patients with suspected RASopathies and to identify predictive clinical "red flags" using machine learning (ML). This retrospective study included patients evaluated at our institution between 2020 and 2023. All patients underwent cardiovascular evaluation, and a subset of individuals with suspected RASopathies underwent genetic assessment including exome sequencing. Thirteen clinical "red flags" were analyzed as predictors of a molecular diagnosis within the subgroup of patients with suspected RASopathies. Diagnostic performance was assessed via sensitivity, specificity, and area under the curve (AUC). A random forest classifier identified the most predictive clinical features. Among 669 patients, 34 were clinically suspected of RASopathy, with a confirmed diagnosis in 24 cases (71%). Noonan syndrome was most frequent (18/24), and PTPN11 was the most commonly mutated gene (n = 13). Pulmonary valve stenosis (PVS) and facial dysmorphisms were the strongest individual predictors of a positive genetic test result. A threshold of ≥ 2 red flags balanced sensitivity (92%) and accuracy (73.5%). ML analysis identified PVS and facial dysmorphisms as the top predictors. A model including only these features achieved an AUC of 0.86 in the derivation cohort. PVS and facial dysmorphisms are key diagnostic indicators for RASopathies and should prompt early genetic testing. While the ML model showed high performance in this derivation cohort, external validation is needed to confirm its generalizability.
von Quednow E, Bragado López S, Martínez González M
… +1 more, Carrascosa-Romero MC
Am J Med Genet A
· 2026 Jul · PMID 41813602
·
Publisher ↗
We describe a male child with a de novo IRF2BPL c.2152del (p.Cys718Alafs*49) frameshift variant presenting with early-onset NEDAMSS and West Syndrome, and compare this phenotype with two previously reported cases carryin...We describe a male child with a de novo IRF2BPL c.2152del (p.Cys718Alafs*49) frameshift variant presenting with early-onset NEDAMSS and West Syndrome, and compare this phenotype with two previously reported cases carrying the same variant. This is the third report of this specific variant and the first to include a comparative phenotypic analysis, highlighting a potentially consistent and severe clinical pattern. The patient was identified through clinical evaluation and exome sequencing (ES) after presenting with early developmental regression and drug-resistant epilepsy. A literature search identified two additional cases with the same variant and a comparative analysis was conducted. The patient showed neonatal axial hypotonia, early neurodevelopmental regression and epilepsy evolving into West syndrome. Brain MRI revealed corpus callosum thinning and hippocampal malrotation. EEG evolved from burst-attenuation to hypsarrhythmia. ES identified a de novo c.2152del IRF2BPL variant. In comparison, all three cases shared profound hypotonia, severe neurodevelopmental impairment, and early-onset epileptic encephalopathy. These findings support the pathogenicity of the c.2152del variant and suggest its potential association with a severe early-onset NEDAMSS phenotype. Generalizability remains limited by the small number of cases, and confirmation requires further clinical and functional evidence.
Sano S, Murai Y, Shimizu K
… +3 more, Nagai Y, Ishizaki R, Honda Y
Am J Med Genet A
· 2026 Jul · PMID 41810698
·
Publisher ↗
Vosoritide, a C-type natriuretic peptide analogue that inhibits FGFR3 signaling, is approved for the treatment of achondroplasia (ACH) from birth in Japan, Australia, and the United States; however, data on neonatal use...Vosoritide, a C-type natriuretic peptide analogue that inhibits FGFR3 signaling, is approved for the treatment of achondroplasia (ACH) from birth in Japan, Australia, and the United States; however, data on neonatal use remain limited. We report two infants with genetically confirmed ACH who received daily subcutaneous vosoritide starting on postnatal days 8 and 9, representing the earliest initiation reported to date. Both patients tolerated treatment in the short term without serious adverse events during inpatient or outpatient monitoring. Despite early initiation, serial magnetic resonance imaging demonstrated progressive foramen magnum stenosis during infancy, and both patients required decompression surgery at 9 and 5 months of age, respectively, consistent with the known natural history of ACH, with an uncomplicated postoperative course in both cases. Growth trajectories, assessed by growth velocity (GV), were generally above the ACH-specific reference medians at comparable ages, while the characteristic slowing of GV during infancy was preserved. These observations are descriptive and hypothesis-generating only and do not support changes in current clinical practice. Further data are required to clarify the potential benefits and limitations of initiating vosoritide therapy during the neonatal period.
Am J Med Genet A
· 2026 Jul · PMID 41804817
·
Publisher ↗
Sotos syndrome is an overgrowth disorder caused by nuclear receptor binding SET domain protein 1 (NSD1) haploinsufficiency, whereas reciprocal 5q35.2q35.3 microduplication produces a reversed phenotype with growth retard...Sotos syndrome is an overgrowth disorder caused by nuclear receptor binding SET domain protein 1 (NSD1) haploinsufficiency, whereas reciprocal 5q35.2q35.3 microduplication produces a reversed phenotype with growth retardation, microcephaly, delayed bone age, and neurodevelopmental delay. We describe a 43-month-old Korean girl born at 36 + 1 weeks with intrauterine growth restriction (birth weight 2200 g, length 46 cm, occipitofrontal circumference 42 cm). At presentation, all growth parameters were below the 10th percentile, with dysmorphic features including epicanthal folds, telecanthus, and a wide nasal bridge. She walked at 14 months but had an approximately 25-month language delay. Chromosomal microarray revealed a de novo 1.8 Mb duplication at 5q35.2q35.3 encompassing NSD1, classified as pathogenic (triplosensitivity score 3). A growth hormone (GH) stimulation test confirmed deficiency (peak GH 9.87 and 6.42 ng/mL). Recombinant human GH therapy (0.033 mg/kg/day) improved growth to the 5-10th percentile after 6 months. This is the first reported Korean case of 5q35.2q35.3 duplication with reversed Sotos phenotype and GH deficiency, which expands the endocrine spectrum of the disorder and underscores the need for early genetic testing and endocrine evaluation. [Correction added after first online publication on 23 March 2026: The dosage of rGH therapy was corrected from "0.1 IU/kg/day" to "0.033 mg/kg/day.].
Uctepe E, Esen FN, Mancilar H
… +3 more, Tümer S, Celebi F, Yesilyurt A
Am J Med Genet A
· 2026 Jul · PMID 41804662
·
Publisher ↗
Interstitial deletions involving 3q27.1 define a distinct microdeletion syndrome characterized by prenatal-onset growth restriction, postnatal microcephaly, hypotonia, intellectual disability, and distinctive craniofacia...Interstitial deletions involving 3q27.1 define a distinct microdeletion syndrome characterized by prenatal-onset growth restriction, postnatal microcephaly, hypotonia, intellectual disability, and distinctive craniofacial features. While AP2M1 haploinsufficiency has been proposed as the primary driver of this phenotype, the full spectrum of dosage-sensitive genes within the locus remains unclear. Here, we report a patient with a de novo heterozygous 3q27.1 microdeletion and delineate a refined minimal smallest region of overlap (SRO) of approximately 189 kb, representing the narrowest critical interval associated with the 3q27.1 microdeletion phenotype to date. Chromosomal microarray and exome-based CNV analysis confirmed the deletion, which encompasses PSMD2, EIF4G1, and POLR2H but excludes AP2M1 and DVL3. The patient exhibited severe intrauterine growth restriction, microcephaly, global developmental delay, and mild dysmorphism, consistent with the established 3q27.1 phenotype. PSMD2 encodes a non-ATPase regulatory subunit of the 26S proteasome, and its loss may disrupt proteasome-mediated protein turnover and neuronal homeostasis. Comparison with previously published cases and an overlapping ClinVar variant (ID: 60129) with similar features supports the pathogenicity of this minimal deletion. Our findings refine the 3q27.1 critical region, propose PSMD2 haploinsufficiency as a likely molecular mechanism underlying growth and neurodevelopmental defects. Further cases and functional studies are needed to confirm PSMD2 causality and clarify the proteasome-related mechanisms underlying 3q27.1 microdeletion syndrome.
Nicastro E, Zuccoli C, Marozzi R
… +8 more, Barletta A, Licini L, Tebaldi P, Casotti V, Stinco M, Pezzani L, Iascone M, D'Antiga L
Am J Med Genet A
· 2026 Jul · PMID 41797663
·
Publisher ↗
Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations. Diagnosis is usually straightforward in symptomatic patients, but can be challenging in children and adolescents with...Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations. Diagnosis is usually straightforward in symptomatic patients, but can be challenging in children and adolescents with mild liver disease, borderline urinary copper excretion, or inconclusive genetic findings. Reduced penetrance of several ATP7B variants and the limited sensitivity of conventional biomarkers further complicate diagnostic assessment. Relative exchangeable copper (REC) has recently emerged as a highly accurate biomarker capable of distinguishing WD from other liver diseases and differentiating homozygotes from heterozygotes. We report a 14-year-old girl presenting with transient neurological symptoms and normal biochemical liver tests, except for markedly low serum ceruloplasmin. Standard urinary copper excretion was normal and only mildly increased after penicillamine challenge. Whole-genome sequencing revealed compound heterozygosity for the pathogenic ATP7B variant p.Gly626Ala and the variant of uncertain significance p.Met665Ile. Despite the inconclusive genotype, REC was markedly elevated (17.04%), indicating early impairment of copper homeostasis. Because REC is not yet validated for diagnosis in asymptomatic children, liver biopsy was performed, demonstrating steatosis and a hepatic copper content of 250 μg/g dry weight, confirming WD. This case illustrates the potential of REC as a sensitive metabolic biomarker able to detect early ATP7B dysfunction and to support diagnosis in patients with borderline biochemical findings or hypomorphic variants such as p.Met665Ile.