KDM3B encodes a histone lysine demethylase and is involved in transcriptional regulation. Patients with heterozygous pathogenic variants in KDM3B are diagnosed with Diets-Jongmans syndrome (DIJOS), a rare autosomal domin...KDM3B encodes a histone lysine demethylase and is involved in transcriptional regulation. Patients with heterozygous pathogenic variants in KDM3B are diagnosed with Diets-Jongmans syndrome (DIJOS), a rare autosomal dominant disorder characterized by intellectual disability, developmental delay, distinctive facial features, and short stature. Here, we report the identification of a novel frameshift variant in KDM3B in a seven-month-old male patient evaluated for small stature, microcephaly, facial asymmetry, and mild gross motor delays. A trio exome with results at 14 months of age identified a de novo pathogenic variant in KDM3B, c.2446del p.(Ser816Valfs*6). At 15 months of age, the patient demonstrated additional clinical findings of mild bilateral epicanthal folds, short philtrum, mildly downslanting palpebral fissures, broad nasal bridge, and mildly simplified ears, while his physical and behavioral development remained age appropriate. This is the youngest known patient with a de novo KDM3B variant identified before 1 year of age. Unlike other DIJOS patients, the current proband does not have signs of significant neurodevelopmental delay. Additionally, he has unilateral facial asymmetry, which had not been previously reported in DIJOS patients. This patient's unique and evolving clinical features further our understanding of the phenotypic diversity and may inform the long-term prognosis of DIJOS.
DNA methylation (DNAm) signatures have emerged as valuable diagnostic biomarkers for rare genetic disorders. To date, the most widely used approach for establishing and validating these signatures has relied on array-bas...DNA methylation (DNAm) signatures have emerged as valuable diagnostic biomarkers for rare genetic disorders. To date, the most widely used approach for establishing and validating these signatures has relied on array-based technologies. However, in clinical diagnostics, there is a growing shift from short-read sequencing (SRS) toward long-read sequencing (LRS) technologies. Recent advances in platforms such as Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) enable direct assessment of DNAm from native DNA, offering improved resolution and reduced technical bias compared to array-based technologies. In this study, we compared DNAm profiles generated by LRS with those obtained from DNAm arrays. DNAm profiles of two individuals with pathogenic KMT2D variants were analyzed using DNAm arrays, LRS using PacBio and ONT, and ONT multiplexed sequencing with adaptive sampling. A support vector machine (SVM) classifier trained on array data, as well as the public classification platform EpigenCentral, yielded correct predictions for all LRS samples, underscoring the potential of LRS platforms in DNAm-based diagnostics. Our results suggest that DNAm profiles generated by LRS align well with DNAm signatures established using DNAm arrays, supporting their feasibility in clinical and research applications with the added benefit of simultaneous methylation and sequence analysis.
The genetic etiology of non-obstructive azoospermia (NOA) characterized by maturation arrest (MA) remains incompletely understood. A homozygous nonsense variant (c.119G>A, p.W40X) in KCTD19 was identified in two unrelate...The genetic etiology of non-obstructive azoospermia (NOA) characterized by maturation arrest (MA) remains incompletely understood. A homozygous nonsense variant (c.119G>A, p.W40X) in KCTD19 was identified in two unrelated probands with NOA. This variant disrupts the evolutionarily conserved BTB domain and leads to the absence of the KCTD19 protein. Histological analysis revealed a complete absence of post-meiotic germ cells in the probands' testes, with spermatogenesis progressed into late prophase I (at least to the zygotene stage) but failed to complete meiotic division. Our findings demonstrate that bi-allelic loss-of-function variants in the meiotic gene KCTD19 cause complete MA. This study highlights an indispensable role of KCTD19 in meiotic prophase I, and expands the genetic spectrum underlying male infertility.
Heterozygous variants in the ACAN gene are a recognized cause of short stature. We aimed to evaluate the response to growth hormone (GH) treatment in members of an extended family carrying an ACAN variant. Clinical and l...Heterozygous variants in the ACAN gene are a recognized cause of short stature. We aimed to evaluate the response to growth hormone (GH) treatment in members of an extended family carrying an ACAN variant. Clinical and laboratory data of five related children were retrospectively collected. GH therapy was initiated at a mean age of 3.2 ± 2.1 years and treated for 6.4 ± 5.0 years. The height standard deviation scores (SDS) increased from -3.3 ± 1.0 to -2.0 ± 1.1 (p = 0.001), with a mean gain of 1.3 ± 0.3 SDS. The most notable increase in growth velocity SDS occurred during the first year of treatment (-0.5 ± 0.6 to 2.1 ± 1.2; p = 0.04). No adverse effects were observed, and bone age did not advance significantly. Three children entered puberty between the ages of 10 and 11.6 years and received adjunctive gonadotropin releasing hormone analog therapy. Genetic testing identified a heterozygous nonsense variant in the ACAN (c.2023C>T; p.Arg675*). Our findings suggest that GH therapy can improve growth velocity in children with ACAN-related short stature, though the degree of response varies even within the same family. The long-term impact on final adult height remains to be elucidated.
Genome sequencing (GS) has emerged as the gold standard for diagnosing patients with rare diseases. As with many emerging technologies, equitable access remains a concern. To evaluate the feasibility and diagnostic impac...Genome sequencing (GS) has emerged as the gold standard for diagnosing patients with rare diseases. As with many emerging technologies, equitable access remains a concern. To evaluate the feasibility and diagnostic impact of expanding access to GS, we report our experience implementing CincyKidsSeq, a prospective study offering GS as a "proband-first" test. Participants of all ages with at least one symptom were referred by genetics or non-genetics healthcare providers, or alternatively, were self-referred from February 2024 to February 2025. This diverse referral structure was evaluated for diagnostic yield while maintaining clinical oversight through a hybrid model in which reportable variants are delivered through genetic providers. The overall diagnostic yield of GS on 313 participants was 22% in the unstratified cohort. Self-referred patients had a higher diagnostic yield (11/33; 33%), compared with patients referred by a non-genetics provider (27/98; 27%), or genetics provider (32/182; 18%). Self-referred individuals were older, more likely to be female, frequently test-naïve, and utilized fewer human phenotype ontology (HPO) terms (p value = 0.0016). Self-referral may serve as an effective and complementary pathway for improving access to GS. Empowering families to initiate GS may be a reasonable pathway for an alternative model for genetic service delivery.
A recurrent de novo germline variant in the MAX gene, p.(Arg60Gln), has recently been associated with polydactyly-macrocephaly syndrome in six unrelated individuals. Affected individuals presented with progressive macroc...A recurrent de novo germline variant in the MAX gene, p.(Arg60Gln), has recently been associated with polydactyly-macrocephaly syndrome in six unrelated individuals. Affected individuals presented with progressive macrocephaly, post-axial polydactyly, developmental delay, autistic features and a series of craniofacial, brain, cardiac, ocular, and renal anomalies. Here, we describe two unrelated female probands with the known recurrent MAX variant, c.179G>A p.(Arg60Gln), who presented with the emerging phenotypes of the MAX-associated syndrome. We also propose that genitourinary abnormalities, including Mayer-Rokitanski-Kuster-Hauser syndrome in one individual, may constitute an expansion of the known phenotype. These findings contribute to the current knowledge regarding the phenotypic spectrum of MAX-associated polydactyly-macrocephaly syndrome.
A homozygous LZTR1 frameshift variant resulting from maternal uniparental disomy of chromosome 22 [UPD(22)] is associated with bone marrow failure and dysmorphic features distinct from those of Noonan syndrome. Biallelic...A homozygous LZTR1 frameshift variant resulting from maternal uniparental disomy of chromosome 22 [UPD(22)] is associated with bone marrow failure and dysmorphic features distinct from those of Noonan syndrome. Biallelic LZTR1 variants lacking the second BTB domain may underlie a rare clinical phenotype characterized by bone marrow failure.
Whole-genome sequencing identifies intronic variants whose pathogenicity can be predicted with tools like SpliceAI. However, an actionable classification of such variants may require RNA-based validation, which can be li...Whole-genome sequencing identifies intronic variants whose pathogenicity can be predicted with tools like SpliceAI. However, an actionable classification of such variants may require RNA-based validation, which can be limited by low expression in clinically accessible tissues. We report two fetuses from one family with Arthrogryposis multiplex congenita 6 (AMC6 [OMIM # 619334]) and biallelic NEB variants: a paternally inherited likely pathogenic frameshift variant, Chr2(GRCh38):g.151579391del; NM_001164508.2:c.16653del; NP_001157980.2:p.(Asp5552ThrfsTer5), and a maternally inherited intronic variant of uncertain clinical significance, Chr2(GRCh38):g.151496267G>A; NM_001164508.2:c.24486+9C>T; NP_001157980.2:p.(?). Because NEB is poorly expressed in fibroblasts, we used CRISPR activation to induce its expression in fibroblasts from the heterozygous mother. RNA-sequencing subsequently confirmed that the intronic variant generated a novel splice donor site associated with inferred loss of splicing at the canonical donor site. After NMD-inhibition, we could thus identify 45.5% of NEB transcripts with a 7 bp exon extension, predicted to result in a protein-coding frameshift. The intronic variant was classified as likely pathogenic, allowing a genetic diagnosis.
Huntington's disease (HD) has prevalent, life-altering consequences for affected individuals, relatives, familial caregivers and systemic functioning. However, the shared psychosocial impacts of HD across family systems...Huntington's disease (HD) has prevalent, life-altering consequences for affected individuals, relatives, familial caregivers and systemic functioning. However, the shared psychosocial impacts of HD across family systems are inadequately understood, and a synthesis of evidence regarding these experiences is currently lacking. This thematic synthesis provides an up-to-date integration of qualitative research describing psychological, social and relational difficulties experienced by HD families. A systematic search across PsycINFO, CINAHL, MEDLINE and Scopus identified nine qualitative studies. Four interconnected superordinate themes were developed, describing a disintegration of HD families from society, HD-related emotional and psychological burdens, an interplay of extrinsic stressors and recalibration of the family system. These findings extend existing knowledge about systemic impacts of HD, highlighting diverse and pervasive psychological and social difficulties faced by families. The synthesis recommends the development of interventions and clinical understandings to appropriately support family systems around psychosocial and relationship dynamic challenges in the unique context of HD.
of prominent clinical features and molecular findings of SENP7-associated disorder in previous cases and our case.of prominent clinical features and molecular findings of SENP7-associated disorder in previous cases and our case.
Biallelic pathogenic expansions in RFC1 contribute to the genetic etiology of PD, with a frequency similar to that of other known autosomal recessive PD genes. RFC1-positive PD is currently not clinically distinguishable...Biallelic pathogenic expansions in RFC1 contribute to the genetic etiology of PD, with a frequency similar to that of other known autosomal recessive PD genes. RFC1-positive PD is currently not clinically distinguishable from RFC1-negative PD, but genetic background may play a role in future therapies or other interventions.
Marchetti GB, Rosina E, Meossi C
… +14 more, Mura M, Pezzani L, Selicorni A, Bedeschi MF, Tenconi R, Agostoni C, Finelli P, De Matteis S, Di Fede E, Massa V, Pezzoli L, Gervasini C, Iascone M, Milani D
Chromatinopathies (CPs) are an expanding group of rare genetic disorders affecting epigenetic machinery. Besides an intricate genotypic spectrum, these conditions share overlapping phenotypes characterized by neurocognit...Chromatinopathies (CPs) are an expanding group of rare genetic disorders affecting epigenetic machinery. Besides an intricate genotypic spectrum, these conditions share overlapping phenotypes characterized by neurocognitive impairment, growth defects and distinctive, but often convergent, facial features. Although individually rare, the landscape of CPs is increasingly growing and represents an emerging and possibly underestimated cause of disability. Due to their complexity and rarity, accurate diagnosis and management pose significant difficulties. To address these challenges and gain a deeper overview of these diseases' spectrum, we retrospectively collected clinical characteristics of 239 patients diagnosed with CPs and critically analyzed their diagnostic journey, growth charts, neurological and gestaltic features. Starting from the largest collection of CPs to date, our data point to wide sequencing analyses as the best shortcut to diagnosis. We have also demonstrated the importance of growth defects in this group of disorders that require dedicated growth tables, and we have delved into the great variability of neurological and clinical burden in these conditions. This retrospective study provides a significant advance in our understanding of these rare diseases and will help to improve diagnostic, therapeutic, and clinical approaches to CPs and to develop personalized multidisciplinary care plans for affected patients.
Marbach-Schaaf neurodevelopmental syndrome (MASNS) is an ultra-rare, monogenic disease caused by pathogenic variation in PRKAR1B, which codes for the R1β regulatory subunit of protein kinase A (PKA), a key effector of cA...Marbach-Schaaf neurodevelopmental syndrome (MASNS) is an ultra-rare, monogenic disease caused by pathogenic variation in PRKAR1B, which codes for the R1β regulatory subunit of protein kinase A (PKA), a key effector of cAMP signaling within the nervous system. This work provides a comprehensive clinical description of 12 subjects with pathogenic PRKAR1B variants, including two individuals with a heterozygous deletion including PRKAR1B, supporting haploinsufficiency as a possible mechanism of disease. Phenotypic information was obtained by interview, using a systematic multi-dimensional questionnaire. Besides expanding the evidence for established MASNS phenotypes like developmental delay, ID, ASD, pain insensitivity, as well as mild dysmorphisms, we broaden the clinical spectrum through the description of new and underreported findings, in particular increased body weight. In addition, the presence of genomic deletions suggests dosage sensitivity of PRKAR1B, demonstrating that both sequence and copy number variants should be considered in diagnostic testing. This work gives valuable insight into the pathophysiology of MASNS and sets a framework upon which to design future mechanistic studies of PKA signaling in brain development.
Mitochondrial DNA depletion syndrome 1 (MTDPS1) is a rare autosomal recessive disorder caused by mutations in the TYMP gene, leading to mitochondrial failure. Hallmark features include gastrointestinal dysmotility, cache...Mitochondrial DNA depletion syndrome 1 (MTDPS1) is a rare autosomal recessive disorder caused by mutations in the TYMP gene, leading to mitochondrial failure. Hallmark features include gastrointestinal dysmotility, cachexia, peripheral neuropathy, ocular signs, hearing loss, and leukoencephalopathy. We present a 39-year-old woman with premature ovarian insufficiency (POI) as a novel endocrine manifestation of MTDPS1. She had normal pubertal development with menarche at age 10. In her mid-20s, she developed fatigue, nausea, vomiting, abdominal pain, weight loss, and amenorrhoea at age 29. Investigations revealed POI with elevated FSH levels, a normal karyotype, negative autoimmune markers. Imaging showed a thin endometrium, small ovaries, osteoporosis, severe gastroparesis. An incidental renal angiomyolipoma prompted an MRI of the brain, revealing symmetrical abnormal white matter changes, suggestive of leukodystrophy. Given diagnostic uncertainty and a history of consanguinity she was referred to clinical genetics and underwent whole genome sequencing which identified a novel homozygous variant (c.559C > T; p.(Gln 187*)) in the TYMP gene, confirming MTDPS1. Though POI is not a well-established feature of MTDPS1, mutations in other genes linked with mitochondrial function are known to be associated with POI and we postulate that this is an endocrine manifestation of MTDPS1. Genetic assessment should be considered in unexplained POI, particularly if associated with other clinical features/consanguinity.
Recently, gain- or loss-of-function variants in the calcium voltage-gated channel subunit alpha1I gene (CACNA1I) have been shown to cause neurodevelopmental disorders. As only 10 cases have been reported to date, clinica...Recently, gain- or loss-of-function variants in the calcium voltage-gated channel subunit alpha1I gene (CACNA1I) have been shown to cause neurodevelopmental disorders. As only 10 cases have been reported to date, clinical information remains limited. This article describes a patient carrying a previously identified CACNA1I variant (NM_021096.4: c.2579T>A, p.Ile860Asn). Notably, our patient exhibited previously unreported clinical findings resembling those observed in disorders associated with other CACNA1 family members, suggesting that these features may be characteristic of this disorder. Brain MRI revealed previously unreported excess iron accumulation in the globus pallidus and substantia nigra. These findings indicate that this disorder may be part of the spectrum of neurodegeneration with brain iron accumulation.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the HTT gene. Existing toxin-induced and genetic models provide important insights, but none fully replicate...Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the HTT gene. Existing toxin-induced and genetic models provide important insights, but none fully replicate the progressive pathology of HD. An AAV9-mediated striatal mouse model expressing mutant HTT with 82 CAG repeats was established to reproduce hallmark neuropathological changes and behavioral deficits. Male C57BL/6 mice received bilateral intrastriatal injections of AAV9-HTT-82Q or control AAV9-GFP. Behavioral performance was assessed by rotarod, balance beam, open field, and Y-maze tests. Neuropathology was examined with HE/Nissl staining, TUNEL assay, and immunofluorescence for mHTT, DARPP-32, GFAP, and Iba1. AAV9-82Q mice exhibited progressive motor coordination deficits on the rotarod from Week 4 and impaired beam traversal from Week 18. Open field testing revealed persistent hyperactivity from Week 8, while anxiety-like and cognitive measures showed only mild, non-significant trends. Histological analysis demonstrated extensive mHTT aggregation in the striatum, accompanied by neuronal pyknosis, vacuolization, and significant loss of Nissl-positive neurons. TUNEL staining confirmed increased apoptosis. Immunofluorescence further revealed selective reduction of DARPP-32+ medium spiny neurons, along with marked astrogliosis and microgliosis, indicating robust neurodegeneration and inflammatory responses. The AAV9-82Q model induces adult-onset, progressive HD-like pathology with early motor impairments, neuronal loss, and glial activation. It complements existing models and provides a reproducible platform for mechanistic studies and preclinical therapeutic evaluation.
We conducted a retrospective chart review of 142 patients with tuberous sclerosis complex (TSC) seen in a multidisciplinary clinic between 2008 and 2023 to describe patients' clinical and genetic characteristics, disease...We conducted a retrospective chart review of 142 patients with tuberous sclerosis complex (TSC) seen in a multidisciplinary clinic between 2008 and 2023 to describe patients' clinical and genetic characteristics, disease severity, therapy, and genetic variations. The most common manifestations of TSC were neurological, dermatological, and renal involvements. Among 100 patients who underwent genetic testing, 26% and 62% were positive for TSC1 and TSC2 variants, respectively, and 12% had no pathogenic variant identified. Specific disease-causing variants in the TSC gene were characterized in 62.0% of patients. As shown in previous studies, patients in our cohort carrying TSC2 variants tended to have more severe and earlier onset symptoms, including higher rates of skin and renal involvement, infantile spasms, and TSC-associated neuropsychiatric disorders. We also identified two distinct clinical subgroups: one characterized by predominant renal involvement and the other by more pronounced neurological manifestations. These groups seem to follow different disease courses, suggesting potential for more personalized monitoring and treatment approaches. Our study revealed key differences between TSC patients with TSC1 and TSC2 variants, but the retrospective analysis warrants further research to identify early indicators predicting TSC disease course.
O'Donnell-Luria-Rodan syndrome (ODLURO) is a rare disorder caused by a pathogenic variant in KMT2E and associated with intellectual disability. To date, the neurobehavioral phenotype of this disorder remains elusive. Her...O'Donnell-Luria-Rodan syndrome (ODLURO) is a rare disorder caused by a pathogenic variant in KMT2E and associated with intellectual disability. To date, the neurobehavioral phenotype of this disorder remains elusive. Here, we aimed to characterize the cognitive and behavioral profiles associated with ODLURO and compare the trends with those of other disorders associated with epigenetic regulation of gene expression at H3K4, Wiedemann-Steiner syndrome (WDSTS) and Kabuki syndrome type 1 (KABUK1). Findings show prominent behavioral features in ODLURO include problems with anxiety (33%), attention (67%), and executive function (50%) (working memory, cognitive inflexibility), with similar severity ratings as WDSTS and KABUK1. Two-thirds of participants were rated in the moderate-to-severe range in overall autism-like behaviors on the SRS-2; however, study findings highlighted a pattern of most day-to-day difficulties in Restricted/Repetitive Behaviors paired with relatively fewer challenges in Social Motivation, comparable to trends reported in WDSTS. Sleep disturbances are common in ODLURO (85%) and associated with behavior regulation difficulties, highlighting the importance of early screening/intervention. In brief, ODLURO shares similarities in neurobehavioral functioning with other disorders of H3K4 modulation of gene expression, warranting further systematic research with cross-syndrome comparisons to elucidate the relationship between epigenetic regulation and pathogenesis of neurodevelopmental disorders.
De novo CCNK missense variant associated with mild intellectual disability, subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), and ventriculomegaly. This case broadens the clinical spectrum of CCNK-related...De novo CCNK missense variant associated with mild intellectual disability, subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), and ventriculomegaly. This case broadens the clinical spectrum of CCNK-related neurodevelopmental disease and supports cyclin K as a disease gene; imaging and phenotype suggest a milder presentation compared with deletions.
We report a novel SCN5A missense variant (c.655C>T (p.Arg219Cys)) in a family with non-dilated left ventricular cardiomyopathy, broadening the spectrum of SCN5A-related structural cardiac diseases. The proband, a 35-year...We report a novel SCN5A missense variant (c.655C>T (p.Arg219Cys)) in a family with non-dilated left ventricular cardiomyopathy, broadening the spectrum of SCN5A-related structural cardiac diseases. The proband, a 35-year-old man, presented with embolic stroke and myocardial fibrosis in the absence of ventricular dilation. He exhibited a significant arrhythmic burden, including premature ventricular complexes and a non-sustained ventricular tachycardia, prompting prophylactic subcutaneous defibrillator implantation. Genetic testing identified a heterozygous SCN5A variant, also present in five relatives with myocardial fibrosis of variable extent on cardiac magnetic resonance imaging. The variant affects a highly conserved residue within the voltage-sensing domain of the Nav1.5 channel and, according to ACMG criteria, is best classified as a variant of uncertain significance. Nevertheless, its segregation with disease and the established functional importance of this region of Nav1.5 suggest a possible role in the observed phenotype. This report highlights a structural cardiomyopathy phenotype potentially linked to SCN5A dysfunction and supports the growing recognition of overlap between ion channelopathies and cardiomyopathies.