Clinical Genetics最新文献

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.

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.

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 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, 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, 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.

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. 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 neurodevelopmental disease and supports cyclin K as a disease gene; imaging and phenotype suggest a milder presentation compared with deletions.