Kwon Y, Kim S, Kim YZ
… +9 more, Jeong TJ, Im M, Ha SY, Jeon TY, Choe YH, Cho SY, Kim MJ, Choi GS, Lee S
Am J Med Genet A
· 2026 May · PMID 42135274
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Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function pathogenic variants in SMAD4 and is now recognized as a progressive multisystem fibrotic disease. Although transforming growth factor-β (TGF...Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function pathogenic variants in SMAD4 and is now recognized as a progressive multisystem fibrotic disease. Although transforming growth factor-β (TGF-β) signaling plays a central role in hepatic fibrogenesis, hepatobiliary involvement in Myhre syndrome has not been systematically evaluated. We report the first case of Myhre syndrome complicated by rapidly progressive biliary cirrhosis requiring liver transplantation in a 15-year-old male with a confirmed SMAD4 p.Ile500Val variant. Following an infectious episode, the patient developed severe cholestasis with imaging and histopathologic findings consistent with fibro-obliterative cholangiopathy, ultimately necessitating living donor liver transplantation. A systematic review of 55 published reports comprising 217 patients with Myhre syndrome revealed that hepatic evaluation was rarely performed and that previously reported liver abnormalities were mild and secondary, most commonly related to right heart dysfunction or metabolic disease, with no prior cases of progressive biliary fibrosis. This case suggests that dysregulated SMAD4-TGF-β signaling may predispose selected organs to fibro-obliterative injury and that infection-driven inflammation may act as a critical trigger for hepatic fibrosis in Myhre syndrome, expanding the recognized spectrum of organ involvement in this disorder.
Am J Med Genet A
· 2026 May · PMID 42135266
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A girl had been seen at 15 months of age for developmental expressive language and gross motor delays and had subsequent serially normal neurological evaluations until age 6 years when she developed a new abnormality of...A girl had been seen at 15 months of age for developmental expressive language and gross motor delays and had subsequent serially normal neurological evaluations until age 6 years when she developed a new abnormality of gait clinically similar to a paroxysmal kinesigenic dyskinesia for which she tested negative. Multiple maternal family members were known to have a pathogenetic variant in N-α-acetyltransferase 10 (NAA10) [c.235C>T (p.R79C)]. The appearance of a gait disorder in association with NAA10-related syndrome has not been previously described and expands the phenotype of this disorder to include this novel neurological symptom. The relevant literature of the very few cases of NAA10-related syndrome that include passing mention of any movement or gait abnormality is reviewed.
Am J Med Genet A
· 2026 May · PMID 42135263
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U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential pre-mRNA splicing factor involved in the early stages of pre-mRNA splicing. To date, multiple individuals have been reported with predominantly heterozygous...U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential pre-mRNA splicing factor involved in the early stages of pre-mRNA splicing. To date, multiple individuals have been reported with predominantly heterozygous missense variants presenting intellectual disability, speech and motor delays, seizures, hypotonia, and thin or hypoplastic corpus callosum. Here, we describe a patient with a de novo 2.2 Mb interstitial deletion involving chromosome 19q13.42-q13.43, encompassing U2AF2, presenting with intellectual disability, epilepsy, corpus callosum hypoplasia, dysmorphic features, and congenital heart disease. The patient's clinical features overlap substantially with those reported in individuals harboring heterozygous U2AF2 variants, supporting haploinsufficiency as a plausible disease mechanism. To our knowledge, this represents the first postnatal report of complete U2AF2 gene deletion. In addition, this is the first detailed phenotypic characterization of a distal 19q chromosomal interstitial deletion, further delineating the clinical spectrum associated with this genomic region.
Macchiaiolo M, Carboni A, Gonfiantini MV
… +4 more, Vecchio D, Biuso A, Lucignani G, Gandolfo C
Am J Med Genet A
· 2026 May · PMID 42124512
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Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder characterized by growth restriction, intellectual disability, skeletal anomalies, and distinctive craniofacial features. We present two pediatric cases of CdLS...Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder characterized by growth restriction, intellectual disability, skeletal anomalies, and distinctive craniofacial features. We present two pediatric cases of CdLS with previously undescribed cerebrovascular malformations. Cerebrovascular anomalies have not yet been systematically reported in CdLS. Both patients share similar clinical features and comparable complex vascular patterns, including a right aortic arch and an isolated common trunk for the left vertebral and subclavian arteries. The left cerebral hemisphere is primarily supplied via contralateral vessels. These findings suggest a potential link between cohesin gene variants and cerebrovascular development, warranting further investigation into the role of these genes in angiogenesis and the neurovascular phenotypes of CdLS.
Am J Med Genet A
· 2026 May · PMID 42124361
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Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder caused by heterozygous pathogenic variants in COL3A1. European studies have shown that celiprolol may reduce the risk of life-threatening...Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder caused by heterozygous pathogenic variants in COL3A1. European studies have shown that celiprolol may reduce the risk of life-threatening vascular events, but outcomes in non-European populations and the therapy's psychological impact remain unclear. We conducted a retrospective cohort study of individuals aged ≥ 20 years with genetically confirmed vEDS in a single referral center in Japan between 2000 and 2024. Clinical, molecular, and treatment data were obtained from medical records, and semi-structured interviews were conducted with a subset of participants to assess patient experiences. Twenty-six patients were included. The mean age at celiprolol initiation was 36.9 years, with a mean follow-up of 96.6 months. All patients received celiprolol, and 61.5% reached the target dose (400 mg/day). One patient died of hepatic artery rupture; vascular events occurred in 11, while 14 remained event-free. No significant associations were observed between vascular event occurrence and genotype or celiprolol dose. Interviews with 11 patients revealed that celiprolol use provided emotional reassurance and promoted a more proactive approach to disease management. Celiprolol therapy may reduce fatal vascular events in vEDS and have a positive psychological impact, though nonfatal vascular complications remain frequent.
Ariyasu D, Kosaki R, Cho H
… +4 more, Nakashima M, Tsuchihashi T, Kosaki K, Yamazawa K
Am J Med Genet A
· 2026 May · PMID 42117603
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Intellectual Developmental Disorder with Speech Delay, Autism, and Dysmorphic Faces (IDDSADF) is a rare neurodevelopmental disorder caused by heterozygous variants in CNOT3. Although several cohorts have been documented...Intellectual Developmental Disorder with Speech Delay, Autism, and Dysmorphic Faces (IDDSADF) is a rare neurodevelopmental disorder caused by heterozygous variants in CNOT3. Although several cohorts have been documented worldwide, no Japanese patients have been reported to date. Here, we present the first two Japanese cases of IDDSADF, an 8-year-old girl and a 19-year-old boy, both presenting with developmental delay, characteristic facial features, and short stature. Both individuals exhibited a thin, tented upper lip, a morphology that has been rarely reported in other cohorts and may represent an ethnicity-associated trait. Growth impairment was observed either from early childhood or emerging after puberty and may represent an underrecognized aspect of the phenotype. Trio-exome sequencing identified pathogenic CNOT3 variants in both patients, including a recurrent frameshift (c.732dup, p.Ser245fs) and a novel splice-site substitution (c.837+1G>A). Our findings expand the phenotypic and mutational spectrum of IDDSADF, highlighting the importance of longitudinal auxological assessment and recognition of potential ethnicity-associated facial traits in its clinical diagnosis and management.
Elsaim S, Vernier B, Truong VTT
… +6 more, Patel RT, Brown M, Portillo MC, Rogge M, Rodriguez-Buritica D, Prakash SK
Am J Med Genet A
· 2026 May · PMID 42112755
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Congenital heart disease (CHD) and dermatologic conditions such as lymphedema and acquired melanocytic nevi (AMN) are common in Turner Syndrome (TS). We hypothesized that abnormalities of cranial neural crest cell deriva...Congenital heart disease (CHD) and dermatologic conditions such as lymphedema and acquired melanocytic nevi (AMN) are common in Turner Syndrome (TS). We hypothesized that abnormalities of cranial neural crest cell derivatives drive the skin and heart manifestations of TS. We conducted joint cardiac and skin examinations of volunteers at a 2023 national TS conference. Electrocardiographic abnormalities were classified according to the Minnesota Codes. Aortic diameters and cardiac anatomy were assessed using a standardized echocardiographic protocol. The primary outcome was the association between ECG abnormalities and thoracic aortic aneurysms (TAA) or CHD. The secondary outcome was the association between AMN counts and CHD, TAA, or the corrected QT interval (QTc). Among 118 participants (median age 33 years; CHD 39%; TAA ~25%), 35% had major ECG abnormalities, most commonly T-wave inversions and ST depressions; QTc prolongation occurred in 7%. Major ECG abnormalities were associated with larger aortic diameter and were more frequent in CHD, with a trend toward increased TAA (OR 2.8). Notably, 17% without known CHD had ECG abnormalities, and > 25% of these had previously unrecognized TAA. Only 45,X karyotype independently predicted ECG abnormalities. AMN burden was markedly elevated and increased stepwise with combined CHD + TAA (adjusted OR per level 13.1) but was not associated with QTc. ECG abnormalities and AMN burden track with cardiovascular disease severity in TS and may identify individuals with unrecognized aortopathy. These preliminary findings support integrated multimodal screening for CHD in TS, pending validation in larger cohorts.
Zhao T, Fennell AP, Sharma T
… +9 more, Bell KM, Dunstan M, Lunke S, McGrath MJ, McLean C, Undiagnosed Diseases Network (UDN‐Aus), Thorburn DR, Stroud DA, Christodoulou J
Am J Med Genet A
· 2026 May · PMID 42109093
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TECPR2 is a key regulator of autophagy, encoded by the TECPR2 gene. Pathogenic variants in this gene have been linked to a rare hereditary sensory and autonomic neuropathy with intellectual disability (HSAN9). We report...TECPR2 is a key regulator of autophagy, encoded by the TECPR2 gene. Pathogenic variants in this gene have been linked to a rare hereditary sensory and autonomic neuropathy with intellectual disability (HSAN9). We report a teenage female with a syndromic intellectual disability disorder associated with neuromuscular abnormalities. Multi-omics analysis including genomics, transcriptomics, and proteomics, together with muscle biopsy from the affected individual, were used in this clinical case. Through trio exome sequencing we identified two heterozygous variants in the TECPR2 gene, NM_014844.4: c.480G>A; p.(Gln160=) and c.2846C>A; p.(Ala949Glu). Both were classified as variants of uncertain significance due to the lack of supporting evidence for pathogenicity. Subsequent long-read sequencing phased the variants and confirmed they were in trans. Additional functional studies using RNAseq and proteomics analyses verified the pathogenicity of the variants. This case study demonstrated the value of a multi-omics assisted analysis, which complemented the traditional phenotype-first approach in reaching a definitive clinical diagnosis.
Wilson R, Somani N, Arias N
… +27 more, Berrocal A, Chen C, Chen X, Cole E, Ehrich P, Faupel TC, Ferrone P, Fete T, Fete M, Fusco F, Goldberg M, Grange DK, Han I, Hartnett ME, King A, Monnet J, Nudleman E, Parraga S, Rosain J, Salois M, Schwaninger M, Spinosa E, Thangarajan S, Van Otterloo E, Wright T, Montezuma S, Campbell JP
Am J Med Genet A
· 2026 May · PMID 42109079
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Incontinentia pigmenti (IP) is a rare, X-linked dominant condition characterized by a perinatal rash as well as abnormalities of the central nervous system (CNS), eyes, hair, nails, and teeth. The CNS and ophthalmic mani...Incontinentia pigmenti (IP) is a rare, X-linked dominant condition characterized by a perinatal rash as well as abnormalities of the central nervous system (CNS), eyes, hair, nails, and teeth. The CNS and ophthalmic manifestations are potentially severe and may lead to neurologic impairment and vision loss. Due to the rarity of IP, there remains a limited understanding of its physiology, and the guidelines for screening, clinical staging, and management of complications remain controversial. To address these gaps, a multidisciplinary, international conference on IP was held in Charlotte, North Carolina, from February 21 to 23, 2025. The meeting was hosted by the National Foundation for Ectodermal Dysplasias and the Oregon Health Sciences University. This report summarizes the discussion and recommendations from the conference, including guidance for screening of ophthalmic complications, as well as next steps for pursuing therapeutic interventions.
Am J Med Genet A
· 2026 May · PMID 42083052
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Gabriele-de Vries syndrome (GADEVS) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in the YY1 gene. Like most rare genetic syndromes, the adult manifestations of GADEVS remain poorly defined....Gabriele-de Vries syndrome (GADEVS) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in the YY1 gene. Like most rare genetic syndromes, the adult manifestations of GADEVS remain poorly defined. Here, we describe the oldest patient reported to date with GADEVS-a 63-year-old woman with a c.1177_1179del YY1 variant, presenting with mild intellectual disability, bilateral cataracts, and early-onset coronary artery disease. We further review the shared and unique features across all adult patients with GADEVS in the literature. Together, this case report and review aim to broaden the phenotypic spectrum of patients with GADEVS.
Porras-Hurtado GL, Mejía-García A, Sinisterra-Diaz SE
… +5 more, Velandia-Piedrahita CA, Geles J, Pachajoa H, Bello S, Gálvez JM
Am J Med Genet A
· 2026 May · PMID 42071326
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Colombia is one of the most genetically diverse populations in Latin America, and its demographic process has promoted the persistence and local enrichment of deleterious alleles, increasing the frequency of autosomal re...Colombia is one of the most genetically diverse populations in Latin America, and its demographic process has promoted the persistence and local enrichment of deleterious alleles, increasing the frequency of autosomal recessive disorders, particularly in semi-isolated Andean populations such as the Eje Cafetero. However, exome-based reference data from this region remain scarce, limiting ancestry-aware variant interpretation and carrier screening strategies. We aimed to characterize the ancestry proportions of this population using exome data, and to estimate the carrier frequency and distribution of pathogenic and likely pathogenic (P/LP) variants in clinically relevant recessive genes. We conducted a cross-sectional study with whole-exome sequencing (WES) in 316 unrelated individuals from the Colombian Eje Cafetero. P/LP variants were evaluated in 454 genes associated with autosomal recessive disorders. The global ancestry proportions were estimated using a validated panel of 250 exome-compatible ancestry-informative markers. Carrier frequencies were compared against Non-Finnish Europeans (NFE) and Admixed Americans (AMX) from gnomAD v4. The cohort showed predominant European ancestry (mean 51%), followed by Native American (36%) and African (13%) components. We identified 151 carriers of 89 distinct pathogenic variants across autosomal recessive genes. The most frequent variants were SERPINA1 c.863A>T (5.5%), CFTR c.1210-11T>G (3.5%), and PYGM c.1094C>T (1.5%). Also, recurrent variants were significantly enriched compared with both NFE and AMX populations, supporting regional founder effects. This study represents one of the most comprehensive exome-based genetic characterizations of the Colombian Eje Cafetero, revealing ancestry-specific enrichment of clinically relevant autosomal recessive variants driven by founder effects.
Cenciarelli S, Marchetti GB, Iascone M
… +9 more, Patricelli MG, Giangiobbe S, Pozzobon GC, Savini MN, Giglio F, Aiuti A, Carrera P, Ferrua F, Peron A
Am J Med Genet A
· 2026 May · PMID 42071175
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Fanconi Anemia (FA) is the most frequent inherited bone marrow failure syndrome. A role for the XRCC2 gene in FA was suspected in 2012 and confirmed in 2016, but only two affected individuals have been described thus far...Fanconi Anemia (FA) is the most frequent inherited bone marrow failure syndrome. A role for the XRCC2 gene in FA was suspected in 2012 and confirmed in 2016, but only two affected individuals have been described thus far, and no long-term follow-up is available. Here we present two young related adults born to consanguineous parents, in whom we identified the homozygous p.(Arg215Ter) variant in XRCC2. Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. Unlike in FA, DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected until the age of 19 and 20 years, respectively. Our report suggests that the homozygous p.(Arg215Ter) variant in XRRC2 causes a distinctive FA-like disorder, characterized by the typical physical characteristics seen in FA, but a lack of major hematological manifestations in childhood, and the presence of a more pronounced neurodevelopmental phenotype than that seen in FA.
Sheyanth IN, Kelly B, Mohanakumar S
… +5 more, Ringgaard S, Dori Y, Nielsen IK, Jensen UB, Hjortdal VE
Am J Med Genet A
· 2026 May · PMID 42071173
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Lymphatic disease represents a well-described manifestation of Noonan syndrome (NS), yet the full phenotypic spectrum remains incompletely characterized, especially in asymptomatic individuals. We conducted a cross-secti...Lymphatic disease represents a well-described manifestation of Noonan syndrome (NS), yet the full phenotypic spectrum remains incompletely characterized, especially in asymptomatic individuals. We conducted a cross-sectional study including 10 individuals with NS (four with peripheral lymphedema and six without) and 10 age- and sex-matched cardiovascularly healthy controls. Central lymphatic anatomy was visualized using non-contrast T2-weighted MR-lymphangiography, and peripheral lymphatic morphology and function were assessed with near-infrared fluorescence (NIRF) imaging and strain gauge plethysmography (SGP). Variations in thoracic duct morphology were observed in 89% (8/9) of NS individuals compared to 20% (2/10) of controls. Thoracic lymphatic classifications (Biko/Dori scale) differed significantly in NS individuals, both with and without lymphedema, compared with healthy controls (p < 0.05). Central lymphatic abnormalities were observed in five of nine NS individuals, including three without clinical signs of lymphatic disease. Abnormal peripheral conduction in collective vessels, characterized by retrograde or absent flow, was detected in all four NS individuals with lymphedema (p < 0.05), while normal conduction was observed in asymptomatic NS individuals and controls. Findings from this study indicate that central lymphatic abnormalities may be present in NS regardless of symptom status, with abnormal peripheral conduction developing later in association with clinically manifest lymphedema. Central lymphatic abnormalities extend beyond clinically apparent disease and broaden the recognized phenotype, highlighting the value of lymphatic imaging for diagnosis and monitoring.
Cinelli G, Della Vecchia S, Bergonzini P
… +16 more, Caramaschi E, Spezia E, Parenti C, Madeo SF, Lucaccioni L, Francesca C, Pugliese M, Raviglione F, Colonna C, Calabrese O, Stanghellini I, Marongiu MC, Biagioni E, Ferrari AR, Battini R, Iughetti L
Am J Med Genet A
· 2026 Apr · PMID 42059486
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Heterozygous variants in the AHDC1 gene are associated with Xia Gibbs Syndrome (XGS), a genetic disorder with a highly variable phenotype. Cognitive impairment, motor delay, language delay, neonatal hypotonia, and sleep...Heterozygous variants in the AHDC1 gene are associated with Xia Gibbs Syndrome (XGS), a genetic disorder with a highly variable phenotype. Cognitive impairment, motor delay, language delay, neonatal hypotonia, and sleep apnea are considered "cardinal" signs of the disease. In a multicenter cross-sectional study, we analyzed the genetic, epileptological, behavioral, and neuroradiological features of 15 patients with XGS harboring heterozygous variants in AHDC1. The phenotype of our patient cohort is almost overlapping with that already reported in the literature. Seizures begin between 2 and 9 years, while EEG is generally characterized by normal background activity with paroxysmal abnormalities in the posterior areas increased by sleep. We systematically analyzed brain imaging findings as the most frequent brain alteration: the thinning of the corpus callosum, followed by posterior fossa malformation and lateral ventricle morphology abnormalities. Regarding psychiatric disorders, we observed neurodevelopmental disorders such as ID, language disorders, Autism spectrum disorders (ASD), and ADHD in preschoolers, followed by a prevalence of externalizing problems during childhood and adolescence. Our study showed that epilepsy and brain anomalies are very common among XGS individuals. MRI changes are nonspecific, but their association with other clinical features of the syndrome can guide early diagnosis. EEG abnormalities are present in all epileptic patients in the temporal-occipital regions with the same characteristics, so we could hypothesize that these abnormalities could represent a recognizable EEG pattern of XGS. Behavioral disorders represent an important problem, and longitudinal evaluations are needed to improve the classification of the psychopathological spectrum in XGS.
Gehin T, Foy M, Carlier R
… +2 more, Renault V, Benistan K
Am J Med Genet A
· 2026 Apr · PMID 42057351
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Hypermobile Ehlers-Danlos syndrome (hEDS), while generally free from severe vascular complications, may occasionally present with cardiac and vascular abnormalities that warrant specific investigation. While studies have...Hypermobile Ehlers-Danlos syndrome (hEDS), while generally free from severe vascular complications, may occasionally present with cardiac and vascular abnormalities that warrant specific investigation. While studies have been conducted on the prevalence of cardiac involvement, none have focused on vascular aspects. This retrospective study was performed to investigate the prevalence of aneurysms in patients diagnosed with hEDS based on the 2017 International diagnostic criteria, to evaluate the need for systematic vascular screening. Fifty-five patients with hEDS were included. All patients had undergone computed tomography angiography of the chest, abdomen, pelvis, and sometimes the head during their initial assessment. The images were analyzed to determine the prevalence of aneurysms, and a potential link to cardiovascular risk factors was examined. Aneurysms were identified in four patients (7.3%). These were located in the thoracic aorta, splenic artery, or the circle of Willis. There was no significant association with cardiovascular risk factors. While this study provides an initial evaluation of the prevalence of aneurysms in hEDS, its results should be interpreted with caution. Our findings highlight the need for larger-scale studies with rigorous methodology to accurately characterize the vascular abnormalities associated with hEDS and determine their clinical significance.
Aldurayhim F, Basit S, Bashir S
… +2 more, Housawi YH, Mir A
Am J Med Genet A
· 2026 Apr · PMID 42057324
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Developmental and epileptic encephalopathies (DEEs) comprise a clinically and genetically heterogeneous group of severe neurodevelopmental disorders, frequently caused by pathogenic variants in genes encoding neuronal io...Developmental and epileptic encephalopathies (DEEs) comprise a clinically and genetically heterogeneous group of severe neurodevelopmental disorders, frequently caused by pathogenic variants in genes encoding neuronal ion channels or synaptic proteins. The fibroblast growth-factor 12 (FGF12) encodes a binding protein for voltage-gated sodium channels. Variants in FGF12 have recently been associated with autosomal dominant DEEs characterized by early-onset epilepsy and neurodevelopmental impairment. We report three patients with a duplication involving exons 1-4 of FGF12 on chromosome 3q28-q29 and systematically review 24 previously published cases of FGF12-related DEE. Clinical features, electroencephalographic findings, neuroimaging data, and responses to anti-seizure medications (ASMs) were analyzed across a total cohort of 27 patients. Eighteen patients carried FGF12 missense variants, including the recurrent pathogenic p.Arg114His variant (n = 14), p.Gly112Ser (n = 2), p.Glu87Lys (n = 1), and one exon 4 missense variant (chr3:g.192335434C>T). Nine patients had copy number duplications involving FGF12. Seizure onset ranged from 1 day to 4 years of age, with 54.1% presenting in the neonatal period. Tonic seizures were the most common seizure type, and 79.1% of patients exhibited moderate to severe intellectual disability. Brain MRI showed mild cerebral and/or cerebellar atrophy in 41.6% of cases. Across reported cases, variable responsiveness to ASMs was observed, with sodium channel blockers including carbamazepine and phenytoin frequently associated with seizure reduction. This study expands the clinical and genetic spectrum of FGF12-related DEE and highlights considerable phenotypic variability across variant types. While treatment responses were heterogeneous, sodium channel blockers were commonly associated with clinical improvement. These findings support cautious consideration of sodium channel targeting therapies in FGF12-DEE and underscore the need for systematic studies to better define genotype treatment relationships.
Nakane E, Ogata H, Saima S
… +4 more, Kondo C, Seki M, Oto Y, Ihara H
Am J Med Genet A
· 2026 Apr · PMID 42052935
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Irritability is a core challenge in Prader-Willi syndrome (PWS). This study investigated the independent contribution of sensory processing to irritability while controlling for clinical and genetic backgrounds in a coho...Irritability is a core challenge in Prader-Willi syndrome (PWS). This study investigated the independent contribution of sensory processing to irritability while controlling for clinical and genetic backgrounds in a cohort of 101 individuals with PWS (77 deletion, 24 maternal uniparental disomy [mUPD]). Caregivers completed the Japanese version of the Short Sensory Profile (SSP-J) and the irritability subscale of the Aberrant Behavior Checklist (ABC-J). Hierarchical multiple regression analysis was performed. In Step 1, age, sex, genetic subtype, and psychotropic medication use explained 22.3% of irritability variance (R = 0.223, p < 0.001). Adding sensory variables in Step 2 explained an additional 38.2% (ΔR = 0.382, p < 0.001), totaling 60.6% (R = 0.606). Auditory filtering (β = 0.262), under-responsiveness/seeking sensation (β = 0.201), and visual/auditory sensitivity (β = 0.194) were significant independent predictors (p < 0.05). Notably, the effect of the mUPD subtype became non-significant after accounting for sensory variables. Sensory processing is a robust predictor of irritability, independent of genetic subtype and medication. Evaluating sensory profiles is essential for environmental adaptations and behavioral interventions in PWS.
da Costa Urbano JC, da Silva Júnior SRP, Castro MAA
… +5 more, Nóbrega PR, de Vasconcelos JTM, Lucato LT, Kok F, Freua F
Am J Med Genet A
· 2026 Apr · PMID 42050746
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Pathogenic TUBB2A variants are known to cause a rare form of autosomal dominant tubulinopathy. Our aim is to expand the phenotypic spectrum of TUBB2A by documenting a milder phenotype caused by a previously unreported pa...Pathogenic TUBB2A variants are known to cause a rare form of autosomal dominant tubulinopathy. Our aim is to expand the phenotypic spectrum of TUBB2A by documenting a milder phenotype caused by a previously unreported pathogenic variant. We report a newly diagnosed case of TUBB2A tubulinopathy with novel clinical findings of ataxia with preserved ambulation into adulthood, in addition to the already characteristic findings of global developmental delay in childhood, cortical malformations, and epilepsy. Informed consent was obtained for this publication. A 40 year-old man presented to the clinic with a history of global developmental delay, intellectual disability, myoclonic epilepsy, cerebellar ataxia and cortical malformations. We performed exome sequencing, which revealed a monoallelic variant in TUBB2A NM_001069.3: c.620 T>C;p.(Leu207Pro) classified as likely pathogenic. TUBB2A variants may cause slowly progressive ataxia along with global developmental delay and epilepsy. This case widens the phenotypical spectrum and provides a new clinical clue for physicians.