Am J Med Genet A
· 2026 Jul · PMID 42392998
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This cross-sectional study investigated mental health conditions, physical functioning, and health-related quality of life (HRQOL) in adults with Léri-Weill dyschondrosteosis (LWD) in Norway. Questionnaires were sent to...This cross-sectional study investigated mental health conditions, physical functioning, and health-related quality of life (HRQOL) in adults with Léri-Weill dyschondrosteosis (LWD) in Norway. Questionnaires were sent to 61 adults registered at the Norwegian Centre for Rare Diseases. The questionnaires included demographics, medical history, depression (PHQ-8), anxiety (GAD-7), pain catastrophizing, activities of daily living (HAQ), and HRQOL (RAND-36 and PROMIS-29). Results were compared with other skeletal dysplasias (SD) and Norwegian general population norms. Twenty-six participants responded. Mean age was 44 years (range 18-72). A prior psychiatric diagnosis was reported by 42%. Clinically significant symptoms of depression (PHQ-8 ≥ 10) and anxiety (GAD-7 ≥ 10) were reported by 27% and 15%, respectively. Almost all participants reported current pain, most commonly back pain (69%) and pain in the upper extremities (62%). Mental health was lower compared to adults with other SDs and general population norms. Physical functioning was the most affected HRQOL domain and was considerably lower than in the general population. This study highlights both psychological and physical burdens in LWD and underscores the importance of assessing mental health, physical function, pain and HRQOL as part of regular medical follow-up across the lifespan in patients with this condition.
Elshafie RM, Alsharhan H, Abulabqah H
… +6 more, Janicijevic A, Alrashidi NH, Omar S, Bastaki L, Almontashiri NAM, Marafi D
Am J Med Genet A
· 2026 Jun · PMID 42381221
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Hyaluronan and proteoglycan link protein 1 encodes HAPLN1, a critical structural protein in the extracellular matrix (ECM), essential for maintaining tissue architecture and integrity. HAPLN1 mediates stable interactions...Hyaluronan and proteoglycan link protein 1 encodes HAPLN1, a critical structural protein in the extracellular matrix (ECM), essential for maintaining tissue architecture and integrity. HAPLN1 mediates stable interactions between hyaluronan and proteoglycans, crucial elements of the ECM that confer structural stability, elasticity, and functional regulation to connective tissues. Aberrations in HAPLN1 expression or function have been implicated in various pathological conditions, including inflammation and tumorigenesis in humans and skeletal dysplasias in mice. To the best of our knowledge, HAPLN1 has not been implicated in human skeletal dysplasia. Herein, we report a novel homozygous missense variant in HAPLN1 in four individuals from an extended consanguineous Kuwaiti family, co-segregating with a skeletal dysplasia phenotype. Affected individuals presented with shortened long bones of both upper and lower limbs, square-shaped iliac wings, narrowed sciatic notches, flattened acetabular roofs, progressive narrowing of the lumbar interpedicular distance with widened intervertebral disc spaces, and short, stubby metacarpal bones. Our findings identify HAPLN1 as a candidate gene underlying a newly described autosomal recessive skeletal dysplasia.
Muniswamy JKR, Van Zele E, Agely A
… +1 more, Muthusamy K
Am J Med Genet A
· 2026 Jun · PMID 42362996
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MYH11-related hereditary type 2 visceral myopathy is a rare smooth muscle disorder typically presenting in infancy with severe gastrointestinal and genitourinary dysfunction. We describe a 73-year-old female with lifelon...MYH11-related hereditary type 2 visceral myopathy is a rare smooth muscle disorder typically presenting in infancy with severe gastrointestinal and genitourinary dysfunction. We describe a 73-year-old female with lifelong symptoms of gastrointestinal and urinary dysfunction, including chronic constipation, neurogenic bladder, recurrent urinary tract infections, gastroparesis, and pelvic organ prolapse. A multigenerational family history revealed similar visceral smooth muscle abnormalities among 14 affected individuals over five generations, suggesting autosomal dominant inheritance. Whole-genome sequencing identified a heterozygous, likely pathogenic variant in MYH11 c.5819del; p.(Pro1940HisfsTer91), consistent with the diagnosis of autosomal dominant type 2 visceral myopathy. This variant causes production of an abnormally elongated myosin-heavy chain, disrupting muscle contractile function. This individual's survival into her eighth decade reflects long-term clinical stability, possibly attributable to the variant's milder effect. We describe the clinical course of the disease, along with a comprehensive review of previously described individuals with the same variant. This case broadens the phenotypic spectrum of MYH11-associated visceral myopathy, demonstrating that late-onset, milder forms can occur and remain compatible with long-term survival with optimal supportive management. Comprehensive genetic evaluation identifies primary disorders, enabling precise diagnosis, tailored management, and informed genetic counseling for complex phenotypes.
Furuta Y, Yano S, Phillips JA
… +4 more, Tinker RJ, Asano E, Juhász C, Li H
Am J Med Genet A
· 2026 Jun · PMID 42361219
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Phenylketonuria (PKU) is associated with neurocognitive and neuropsychological symptoms despite early treatment and well-controlled phenylalanine (Phe) levels. PKU impairs the conversion of Phe to tyrosine and causes exc...Phenylketonuria (PKU) is associated with neurocognitive and neuropsychological symptoms despite early treatment and well-controlled phenylalanine (Phe) levels. PKU impairs the conversion of Phe to tyrosine and causes excess phenylalanine to accumulate. This accumulation can competitively block some other amino acids from entering the brain. This may reduce production of key neurotransmitters like dopamine and serotonin, which can affect brain function and development. However, direct correlations between blood Phe levels and central nervous system (CNS) neurotransmitter concentrations have not been established, and reliable CNS biomarkers are lacking. Positron emission tomography (PET) enables in vivo assessment of brain metabolism and neurotransmitter-related processes; therefore, we aim to investigate its potential value as a biomarker. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to April 25, 2026. Studies evaluating brain PET imaging in individuals with PKU or hyperphenylalaninemia were included. Data on study design, patient characteristics, PET tracers, and key findings were extracted and synthesized qualitatively. A total of 380 records were screened, and 13 studies were included, with a mean sample size of 8.8 (median 6). PET tracers included fluorodeoxyglucose (FDG), amino acids, including tyrosine-, methionine-, leucine-, aminocyclohexanecarboxylate-based tracers, and fluorodopa-related tracers. FDG PET studies demonstrated regionally heterogeneous abnormalities in brain glucose metabolism, independent of plasma Phe levels. Amino acid PET studies demonstrated reduced cerebral protein synthesis associated with impaired large neutral amino acid transport and increased brain Phe levels. Fluorodopa-related PET studies indicated reduced dopaminergic activity, with no significant correlation between plasma Phe levels and striatal fluorodopa utilization. PET is a promising tool to bridge the gap between peripheral biochemical markers and CNS dysfunction in PKU. Further studies are needed to overcome limitations which include small sample sizes, heterogeneous metabolic control, restricted availability of tracer types, predominantly cross-sectional study designs, and lack of correlation with clinical signs and symptoms.
Bar-Hakim M, Abramovich A, Via-Dorembus S
… +10 more, Heimer G, Ben-Zeev B, Adam E, Barg AA, Roth J, Sheick-Yousif B, Berkowiz RB, Feldon M, Bassan H, Hausman-Kedem M
Am J Med Genet A
· 2026 Jun · PMID 42337932
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Heterozygous germline variants in CBL disrupt its function as a negative regulator of the Ras/MAPK pathway, classically predisposing to Juvenile myelomonocytic leukemia (JMML) and moyamoya. We describe two affected sibli...Heterozygous germline variants in CBL disrupt its function as a negative regulator of the Ras/MAPK pathway, classically predisposing to Juvenile myelomonocytic leukemia (JMML) and moyamoya. We describe two affected siblings carrying a paternally inherited CBL variant (c.1210 T> C, p. Cys404Arg) who exhibited markedly divergent phenotypes, uncovering novel neuroinflammatory and systemic vascular fragility manifestations. The older sibling, a previously healthy 4-year-old girl, presented with acute, rapidly progressive acute disseminated encephalomyelitis (ADEM)-like neuroinflammatory disease post-febrile illness, accompanied by optic neuritis, and severe dystonia-parkinsonism. She had mild splenomegaly and thrombocytopenia. Brain MRI demonstrated extensive bilateral basal ganglia and diffuse white matter abnormalities, without evidence of moyamoya. Cerebrospinal fluid analysis showed pleocytosis and elevated protein, with extensive infectious and metabolic workups returning negative. Conversely, her 2-year-old sister presented with hematologic myeloproliferation and was diagnosed with JMML at 12 months. At 21 months, following an intercurrent viral infection, she presented with recurrent, bilateral arterial ischemic stroke and was diagnosed with severe, bilateral moyamoya. Vessel wall Imaging showed no enhancement. During hospitalization, she demonstrated profound systemic vascular fragility, manifested by a radial artery pseudoaneurysm post-puncture and a femoral artery pseudoaneurysm post-angiography, which required surgical repair. Bilateral encephaloduroarteriosynangiosis led to clinical stabilization. These cases extend the phenotypic spectrum of CBL-related disorders to include severe central nervous system immune dysregulation and systemic vascular fragility with recurrent peripheral arterial pseudoaneurysms. These findings demonstrate that CBL loss of function drives tissue-level proliferative and inflammatory remodeling, highlighting a novel intersection between dysregulated Ras/MAPK signaling, neuroinflammation, and structural vascular vulnerability.
Taşdelen E, Tekbaş UC, Kolkıran A
… +3 more, Çetinkaya S, Kılıç M, Sezer A
Am J Med Genet A
· 2026 Jun · PMID 42316479
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Exome sequencing (ES) has improved Mendelian disease diagnosis, but in consanguineous populations, biallelic variants in typically dominant genes remain underrecognized. This study characterized their clinical and molecu...Exome sequencing (ES) has improved Mendelian disease diagnosis, but in consanguineous populations, biallelic variants in typically dominant genes remain underrecognized. This study characterized their clinical and molecular features and explored pathway-level patterns of dual inheritance. Exome data from 1450 individuals analyzed between 2022 and 2024 were retrospectively reviewed. Biallelic variants were filtered in genes annotated as autosomal dominant in OMIM. A pathway-based analysis using Gene Ontology and STRING identified functionally related genes, and those showing both dominant and recessive inheritance were further evaluated with gnomAD constraint metrics to explore shared mechanisms. Five consanguineous families carried biallelic variants in genes typically associated with dominant inheritance, accounting for ~3.1% of all homozygous pathogenic variants. Mechanisms included hypomorphic effects (TERC, ASH1L), semidominant dosage sensitivity (LRP5), structural or positional effects (FBN1), and complete loss of function with pleiotropy (SMAD6). Pathway analysis revealed dosage-sensitive dynamics in telomere maintenance, extracellular matrix, Wnt/BMP signaling, and histone modification, supporting dual-inheritance behavior driven by gene dosage and functional impact. Our findings show that genes labeled autosomal dominant can also cause disease biallelically, reflecting a dosage-sensitive continuum. Including such analyses in diagnostic pipelines, especially in consanguineous populations, can refine understanding of inheritance in rare disorders.
Am J Med Genet A
· 2026 Jun · PMID 42311177
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The WDR81 and WDR91 genes are important for endosome conversion, fusion, recycling, and transport. Variants in the WDR81 gene have been reported in human patients with cerebellar ataxia, impaired intellectual development...The WDR81 and WDR91 genes are important for endosome conversion, fusion, recycling, and transport. Variants in the WDR81 gene have been reported in human patients with cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome type 2 (CAMRQ2, MIM #610185) and in patients with congenital hydrocephalus with brain anomalies type 3 (HYC3, MIM #617967). Both phenotypes are transmitted in an autosomal recessive inheritance pattern. Loss-of-function type variants in the WDR91 gene have also been recently described in patients with brain malformations such as hydrocephalus, brain atrophy, corpus callosum agenesis, micro-lissencephaly, and cerebellar hypoplasia. However, the literature is scarce, and this association has not been cataloged in the Online Mendelian Inheritance in Man (OMIM) database. Herein, we report a novel homozygous nonsense variant in the WDR91 gene in a child with severe congenital communicating hydrocephalus, Dandy-Walker malformation (not described before in association with this gene), cerebellum hypoplasia, and facial dysmorphism. Exome sequencing (trio) revealed a novel homozygous variant c.1245_1246delAG (transcript ID NM_014149.4) in the WDR91 gene predicted to lead to premature termination variant p.(Arg415Serfs*64). The variant was confirmed on Sanger sequencing in the proband and the asymptomatic parents were shown to be heterozygous for the same variant, demonstrating autosomal recessive inheritance. A review of medical literature revealed that in mice, global Wdr91 knockout causes neonatal death, whereas brain-specific Wdr91 inactivation impairs brain development and causes marked neuronal loss in the cerebrum and cerebellum. We show that as per the Clingen guidelines for gene-disease assertion, the evidence for loss-of-function variants in the WDR91 gene leading to congenital hydrocephalus is strong and supports its inclusion in the OMIM database.
Grosmaitre C, Le Bellego M, Boddaert N
… +2 more, Chaste P, Hadchouel A
Am J Med Genet A
· 2026 Jun · PMID 42286830
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ImportancePulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by alveolar surfactant accumulation leading to respiratory impairment. MARS1 mutations lead to an early onset PAP associated in a...ImportancePulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by alveolar surfactant accumulation leading to respiratory impairment. MARS1 mutations lead to an early onset PAP associated in a setting of multi-organ involvement and respond to high-dose methionine supplementation. While pulmonary manifestations of MARS1-related PAP and their response to methionine are well documented, its potential impact on cognitive and adaptive functioning in pediatric patients remains poorly understood. Understanding the neurodevelopmental profile of children with MARS1-related PAP is essential for optimizing comprehensive care and long-term outcomes. ObjectiveTo characterize the neurodevelopmental profile of children with MARS1-related PAP by assessing intellectual functioning and adaptive behavior using standardized neuropsychological measures and parent-reported questionnaires. DesignObservational cohort study including 16 pediatric patients with MARS1-related PAP aged 14 months to 7.3 years, followed at the Necker-Enfants Malades Hospital (Paris, France) and treated with methionine. Intellectual functioning was assessed using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) when age-appropriate, and adaptive behavior was evaluated via the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) through parent interviews. ResultsSixteen children with MARS1-related PAP underwent the full evaluation. Methionine was started at a median age of 6 months (IQR [5, 15]). Eight of them were able to undergo the WPPSI-IV assessment. The mean Full-Scale IQ was 72.25 (SD = 16.85), indicating borderline to mild intellectual disability relative to normative data. Adaptive behavior composite scores on the VABS-II averaged 69.75 (SD = 23.58), reflecting significant deficits across communication, daily living skills, socialization, and motor domains. The neurodevelopmental impairments were relatively homogeneous across the cohort. ConclusionsChildren with MARS1-related pulmonary alveolar proteinosis exhibit marked impairments in intellectual and adaptive functioning, suggesting a consistent neurodevelopmental profile associated with the disease, and despite methionine supplementation. These findings highlight the need for routine cognitive and developmental monitoring in pediatric PAP patients and support the development of multidisciplinary interventions addressing both respiratory and neurodevelopmental outcomes.
Crain C, Northrup H, Farach LS
… +4 more, Mullegama SV, Shields K, Von Allmen G, Richardson K
Am J Med Genet A
· 2026 Jun · PMID 42286426
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DNM1 encephalopathy is a rare autosomal dominant genetic condition characterized by a range of neurological and developmental manifestations. The typical phenotype is severe, including profound intellectual disability, t...DNM1 encephalopathy is a rare autosomal dominant genetic condition characterized by a range of neurological and developmental manifestations. The typical phenotype is severe, including profound intellectual disability, treatment-resistant epilepsy, ataxia, and structural brain abnormalities. However, milder presentations have increasingly been reported, suggesting that the full phenotypic spectrum remains incompletely defined. We describe the case of a female patient who presents only with well-controlled epilepsy and mild dysmorphic features. Trio exome sequencing identified a de novo likely pathogenic variant in the GTPase domain of DNM1, supporting the diagnosis of DNM1 encephalopathy. Historically, disease-causing variants in the GTPase domain were thought to confer a more severe presentation. However, our patient demonstrates a more attenuated phenotype than previously reported cases, including those viewed as mild, which have consistently included some degree of developmental impairment. This supports an expanded and more variable phenotypic spectrum of DNM1 encephalopathy than previously recognized. This additionally complicates domain-based prognostication; though further cases will aid in elucidating genotype-phenotype correlation.
diMonda J, Al-Jaberi R, Khader MA
… +8 more, Pio T, Briones M, Gill A, Hawkins CM, Kesselman A, Shah J, White M, Sanchez-Russo R
Am J Med Genet A
· 2026 Jun · PMID 42271477
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Genotyping in patients with vascular malformations and/or somatic overgrowth guides precision treatment and is often required for insurance approval of targeted medications. Despite commonly accepted guidelines, uniform...Genotyping in patients with vascular malformations and/or somatic overgrowth guides precision treatment and is often required for insurance approval of targeted medications. Despite commonly accepted guidelines, uniform implementation of genetic testing in this population is hindered by practical challenges in the clinical setting. Here we compare the molecular diagnostic yield as a function of biopsy source, specifics of genetic testing, and type of insurance. We conducted a retrospective chart review of patients who had genetic testing performed at various commercial or academic laboratories on a biopsy for vascular malformations and/or somatic overgrowth. Diagnostic yield was compared by specimen type, depth of coverage (DOC), and billing method. 70 genetic tests were reviewed for 56 patients. High DOC testing yielded a significantly higher diagnostic rate of 74.3% compared to 20.0% in low DOC testing (p < 0.001). Core biopsies (vs. skin punch) and tests utilizing private insurance/institutional billing (vs. Medicaid) also showed a higher diagnostic yield. In the clinical setting, patients reliant on low DOC commercial testing due to insurance barriers face significantly lower diagnostic rates, underscoring a clear inequity in diagnostic outcomes and demonstrating a need for improved testing access.
Am J Med Genet A
· 2026 Jun · PMID 42260322
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Measuring health, a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity, in Down syndrome (DS) was recently achieved through creation of a new health measure. Howe...Measuring health, a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity, in Down syndrome (DS) was recently achieved through creation of a new health measure. However, additional information on health-related medical topics and how health measurement varies in demographic groups from that cohort has not been presented. We surveyed caregivers of individuals age 0-21 with Down syndrome (DS) from a national sample about the health of their son or daughter with DS as part of a broader study to create a valid, reliable health measure in DS. In this manuscript, we present secondary analysis of survey items on health-related topics including co-occurring medical conditions, recurrent infections, and healthcare maintenance. We then conducted an analysis to compare caregiver-reported demographic traits to total health scores through regression modeling to identify predictors of health status. Survey responses from 542 caregivers of individuals with DS were received; rates of co-occurring medical conditions generally aligned with past results, rates of recurrent infections showed lower rates of persistent fungal infections in our cohort (p < 0.0001) and completion of healthcare guidelines did not correlate with health scores (p = 0.13). In regression modeling, parent sex of respondent (male) and better parent health correlated with better total health scores of individuals with DS. Health-related topics show prevalence rates aligning with past literature, lower rates of some infections, and imperfect guideline adherence. Fathers and parents who feel that they are in better health reported better health of their sons and daughters with DS. Trial Registration: ClinicalTrials.gov, NCT04631237.
Subbotin D, Voskanyan A, Borovikov A
… +4 more, Marakhonov A, Bobreshova A, Rosales-Sabino M, Murtazina A
Am J Med Genet A
· 2026 Jun · PMID 42244138
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Distal myopathies (DM) are clinically and genetically heterogeneous neuromuscular disorders, and identifying a molecular genetic cause may remain challenging in a subset of cases. Moreover, DM may be misdiagnosed as here...Distal myopathies (DM) are clinically and genetically heterogeneous neuromuscular disorders, and identifying a molecular genetic cause may remain challenging in a subset of cases. Moreover, DM may be misdiagnosed as hereditary neuropathies due to overlapping clinical features. Here, we report a novel structural variant in FLNC associated with DM identified through genome sequencing (GS). Two affected relatives initially presented independently with referral diagnoses of Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Clinical re-evaluation led to a change of the diagnosis to DM. Muscle MRI revealed a consistent pattern of selective muscle involvement characteristic of DM, enabling identification of six affected individuals within the family. GS was performed in seven family members, including six affected individuals and one unaffected relative. The analysis identified an insertion of two inverted fragments derived from the adjacent intron 2 into exon 3 of the FLNC gene. This complex rearrangement was accompanied by short non-templated nucleotide insertions at the junctions and a 3-bp exonic deletion at the insertion site, ultimately resulting in a frameshift. The structural variant was segregated with disease and was confirmed by Sanger sequencing and one Oxford nanopore long-read sequencing. Our findings expand the mutational spectrum of FLNC-associated disorders and highlight the importance of GS combined with a detailed clinical examination for the diagnosis of DM.
Am J Med Genet A
· 2026 Jun · PMID 42231755
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Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder involving self-resolving joint contractures that are present since birth. Because of characteristic facial features, clinical diagnosis may be suspec...Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder involving self-resolving joint contractures that are present since birth. Because of characteristic facial features, clinical diagnosis may be suspected by experienced clinicians or identified using facial recognition-based software. Confirmation by identification of disease-causing biallelic variants in SCARF2 can be helpful to definitively provide a clinico-molecular diagnosis to differentiate VDEGS from other disorders with overlapping phenotypes with blepharophimosis, arachnodactyly, and camptodactyly. Most affected individuals do not have major malformations or intellectual disability. However, occasional patients with ophthalmological, genitourinary, or laryngeal abnormalities are reported, indicating the need for a detailed evaluation. The causative gene, SCARF2, is located within the region of the 22q11.2 microdeletion syndrome. Two cases with microdeletion of the region on one chromosome and a SCARF2 variant on the other chromosome have been reported. Two cases resembling the phenotype but with no causative variants in SCARF2 have been reported, supporting the possibility of another causative gene with overlapping phenotype. Though prognosis can often be positive, there is a need for better long-term outcome data.
Muda A, Belmessieri B, Accorsi P
… +3 more, Galli J, Errichiello E, Giordano L
Am J Med Genet A
· 2026 Jun · PMID 42226002
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Pathogenic variants in PUS7, encoding pseudouridine synthase 7, cause a rare neurodevelopmental disorder marked by intellectual disability, microcephaly, short stature, and behavioral disturbances. Since the first report...Pathogenic variants in PUS7, encoding pseudouridine synthase 7, cause a rare neurodevelopmental disorder marked by intellectual disability, microcephaly, short stature, and behavioral disturbances. Since the first report in 2018, only 16 patients have been described. We report a novel case with a homozygous pathogenic PUS7 variant and present an updated review of all cases published between 2018 and 2025. Across 17 cases, the most frequent features were moderate/severe intellectual disability, delayed/absent speech, aggressive behavior, microcephaly, mild facial dysmorphisms, motor delay, and short stature. These features are common but non-specific, with the exception of aggressiveness that manifests at a very early age. Less common but more peculiar findings included sensorineural hearing loss, autistic traits, self-injurious behavior, and motor stereotypies. The combination of core features with these more specific symptoms should prompt suspicion of a PUS7-related disorder. We recommend looking for PUS7 pathological variants when performing whole exome sequencing in children with this constellation of neurodevelopmental and behavioral signs.
Risgaard KA, Farach L, Northrup H
… +4 more, Wilson SL, Pearson D, Hashmi S, Richardson K
Am J Med Genet A
· 2026 Jun · PMID 42223173
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Tuberous sclerosis complex (TSC) is a genetic condition with multisystem neurocutaneous signs, including hamartomas, epilepsy, and neuropsychological difficulties. Although sleep disorders are increasingly recognized in...Tuberous sclerosis complex (TSC) is a genetic condition with multisystem neurocutaneous signs, including hamartomas, epilepsy, and neuropsychological difficulties. Although sleep disorders are increasingly recognized in TSC, they remain poorly described in adults. Additionally, the influence of clinical features and commonly used medications on sleep is not well understood. This study assessed sleep disorders in adults with TSC and examined contributing clinical and treatment factors. Adults were recruited through the TSC Alliance and the TSC Center of Excellence (CoE) at UTHealth Houston. Sleep quality was assessed using the Pittsburgh Sleep Quality Index, and demographic, clinical, lifestyle, and medication information was collected from 84 adults. Descriptive and inferential statistics were applied, with significance set at p < 0.05. Overall, 64% (n = 54) met criteria for poor sleep, significantly higher than rates reported in neurotypical adults (p < 0.001). Participants with mental illness or anxiety more frequently reported sleep issues (p = 0.009, p = 0.04). Poor sleep was also associated with use of mTOR inhibitors, antiepileptic drugs, and antidepressants (p = 0.016, p < 0.001, p = 0.045). These results highlight sleep disruption as a common and clinically relevant feature of TSC and emphasize the need for providers to assess sleep carefully, considering both clinical signs and medication effects when developing management plans.