Clinical Genetics最新文献

Mitochondria-associated paraplegin dysfunction is primarily linked to spastic paraplegia; however, genetic alterations in SPG7 have been associated with a broader spectrum of clinical symptoms. To identify disease-causing variants in the SPG7 gene, 437 patients with spastic ataxia, mitochondrial dysfunction-associated symptoms, or motoneuron lesions detected by EMG have been tested. We aimed to assess the clinical spectrum and determine the frequency of damaging variants within patient groups, particularly those less studied. Using ACMG criteria, we identified 10 pathogenic or likely pathogenic variants, 5 variants of uncertain significance with predicted damaging effects, and a probable risk factor variant in 58 patients. We identified 25 biallelic and 33 monoallelic cases. The most common variant was p. Leu78Ter (N = 23), followed by p. Ala510Val (N = 21). The point prevalence of SPG7-associated conditions in Hungary in 2024 is 0.46 per 100 000. In addition to well-characterized cohorts, SPG7 alterations were frequently identified in cohorts with multisystemic mitochondrial disease and lower motoneuron lesions. Multiple mtDNA deletions and histological abnormalities were consistently observed across all groups. In monoallelic cases, no evidence of a digenic effect involving AFG3L2 was found. Both autosomal dominant and recessive inheritance patterns were documented, with monoallelic cases typically presenting with a milder phenotype.

Bone morphogenetic protein 2 (BMP-2), encoded by the BMP2 gene located in chromosomal region 20p12, is a signalling protein involved in formation of bone and cartilage and other developmental processes such as cardiac and neural development. Haploinsufficiency of BMP2 has been associated with distinct facial features, short stature, skeletal malformations and cardiac abnormalities. The degree of developmental delay is still controversial. We summarise clinical and genetic findings from seven individuals with BMP2 haploinsufficiency. The study participants were identified by genetic testing and their phenotypic data was collected retrospectively from medical records. One individual had a novel frameshift variant in BMP2, and six individuals had 1.3-3.7 Mb microdeletions, including BMP2. In our cohort, delayed language development (4/5) and secretory otitis media (4/5) were common. Our results, together with previous studies, suggest that individuals with sequence variants or small microdeletions can have mild developmental delay or delay in one area (e.g., verbal development or gross motor development). We propose that global developmental delay is either a rare part or not part of the phenotype. Based on our observations, we propose that evaluation of language development and regular controls of the middle ear should be included in the surveillance of these individuals.

(Likely) pathogenic variants in NR2F1 are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS, OMIM #615722), a rare neurodevelopmental disorder. Patients present with a variety of symptoms, including intellectual disability, developmental delay, visual impairment, muscular hypotonia, seizures, and/or autistic features. Since it was first described in 2014, the phenotype has steadily expanded. However, there is limited information regarding the natural course of the disorder. Here, we present data on genetic variants and phenotype development of 47 individuals who responded to our questionnaire. A questionnaire was developed to assess the phenotype more comprehensively and to better understand the course of symptoms. In addition, families sent medical documents and photographs. To investigate the genotype-phenotype correlation in our cohort, we compared clinical features of two genotypically distinct groups (variants in the DNA-binding domain (DBD, n = 17) versus variants elsewhere in the gene (n = 30)). We observed a range of common symptoms including developmental delay, muscular hypotonia, optic atrophy, nystagmus, strabismus, autistic features, and thin corpus callosum on brain MRI. Overall, more improvement than worsening was reported. Individuals with variants in the DBD showed a higher prevalence of severe clinical features, such as infantile spasms (46.7% vs. 3.8%, p = 0.002) or nonverbality (50% vs. 3.4%, p = 0.0004), age at diagnosis was statistically significantly different between the two genotypic groups (mean 4.7 years vs. 8.9 years, p = 0.048). Our study confirms characteristic clinical features of BBSOAS. Variants in the DBD are associated with a more severe clinical phenotype. We found no evidence that the disease progresses; rather, several symptoms are reported to improve over time. However, prospective longitudinal studies are needed to further investigate disease progression.

In 2016, Sifrim and colleagues described the first group of patients carrying heterozygous pathogenic variants in CDK13 and sharing major clinical features mainly consisting of congenital heart defects, intellectual disability and peculiar facial features (Congenital Heart Defects, Dysmorphic Facial Features, and Intellectual Developmental Disorder; CHDFIDD, OMIM # 617360). This condition is generally referred to as CDK13-related disorder, and since then other reports have provided further clinical and molecular information. Here we describe a group of 27 previously unreported patients to more accurately profile the clinical spectrum associated with CDK13 variants, disclosing novel associated findings, such as complex craniosynostosis and variable skeletal features (e.g., cranio-cervical anomalies). We also focused on the ocular phenotype that appears to include bilateral congenital glaucoma, posterior embriotoxon, buphthalmos and Duane anomaly. Finally, we observed two cases of mother-to-daughter transmission. Our work clarifies some novel features of CHDFIDD, defines the differential diagnosis of this disorder, and provides recommendations for its clinical management.

Variations in foot arch morphology, including flat feet (pes planus) and high arches (pes cavus), range from asymptomatic to debilitating. Limited research exists on the genetics of foot arch geometry. This systematic review aims to identify single nucleotide polymorphisms (SNPs) linked to foot arch morphology. The review protocol was registered in PROSPERO (CRD42024537877). PubMed, The Cochrane Library, Embase, and Web of Science were searched for studies on SNPs related to foot arch morphology published up to December 2023. Nineteen eligible studies (2006–2020) identified 137 SNPs across conditions affecting connective tissue (12 studies, e.g., Marfan Syndrome), nerves (six studies, e.g., Charcot–Marie–Tooth Disease), and muscles (one study, e.g., Distal Arthrogryposis Syndromes). While no studies directly linked SNPs to foot arch morphology, three explored SNPs in genetic diseases associated with foot arch variations. Pes planus was linked to connective tissue disorders, and pes cavus to neuropathies and myopathies. Only two replicated SNPs were found. This review found no direct studies of SNPs influencing foot arch morphology, highlighting a significant research gap. Future research should examine SNPs in larger cohorts to differentiate natural variations from pathology-driven deformities. To enhance reproducibility, standardized methodologies, and a unified genetic database (including phenotypic data on common traits) should be developed.

Cystatin B gene (CSTB) is responsible for the most common childhood onset type of progressive myoclonic epilepsy (EPM1A). More recently, biallelic CSTB variants were described in four patients with a neonatal onset phenotype of microcephaly, diffuse hypomyelination, brain atrophic changes, and dyskinesia. Herein, we describe the clinical and molecular characterization of five additional patients in whom exome sequencing detected a splice variant (c.67-1G>C) in Family I and II and a missense variant (c.10G>C, p.Gly4Arg) in Family III and IV. Interestingly, these variants were described before in patients with EPM1A. However, all our patients had progressive microcephaly, developmental delay, and dyskinesia. In addition, only one patient developed seizures. Brain imaging showed mainly diffuse hypomyelination and progressive cerebral and cerebellar atrophy of variable severity. Interestingly, one patient showed intracranial calcification and another showed congenital distal arthrogryposis. Our findings support the association between CSTB variants and the neonatal form as a distinct neurodevelopmental phenotype. This newly characterized neonatal onset of the CSTB shares many overlapping features with genetic disorders encompassing microcephaly and hypomyelination.

Intrahepatic cholestasis of pregnancy (ICP) has a multifactorial pathophysiology involving genetic, endocrine, and environmental factors. It is associated with maternal distress and adverse foetal outcomes. The monogenic aetiology of ICP remains unexplored in the Maltese population. We apply whole exome sequencing in 20 unrelated index cases to assess the molecular spectrum of variants in genes linked to bile acid transport. We shortlisted five unique heterozygous variants. Three ABCB4 variants, including a novel likely pathogenic stop-gain variant were detected. Three genealogically unrelated cases carried an ABCB4 p.Asn510Ser variant, suggestive of a founder through shared haplotype analysis. This study provides preliminary insight into the monogenic aetiology of ICP from an unstudied population. It expands the spectrum of genetic variants associated with ICP and provides evidence for a founder effect in the Maltese population.

Steroid-resistant nephrotic syndrome (SRNS) is a severe kidney disorder linked to over 60 genes, including NUP85, which plays a key role in nuclear pore function and glomerulogenesis. We identified a novel homozygous NUP85 variant (NM_024844.5: c.1379G > A, p.Arg460Gln) in a pediatric SRNS patient who also presented with cleft lip-palate and mild intellectual disability, marking the first reported association of these phenotypes with a NUP85 variant. Molecular dynamics simulations revealed that the variant destabilizes the protein's helix bundle, providing mechanistic insights into its potential pathogenic effects. This study broadens the known phenotypic spectrum of NUP85-related conditions and highlights the value of computational tools, such as molecular dynamics, in unraveling the impact of novel variants.

Dynamin-1 is an essential enzyme involved in the recycling of synaptic vesicles, in particular in the scission of endocytic buds within the pre-synaptic terminal. Heterozygous pathogenic variants in DNM1 result in Developmental and Epileptic Encephalopathy type 31A, where patients exhibit early onset refractory epilepsy, severe-profound intellectual disability and poor visual behaviour. We present data demonstrating that this disorder progressively affects retinal synaptic function which, to our knowledge, is the first report of this phenotype in human. Clinical notes of the proband were reviewed incorporating ophthalmic phenotyping (imaging, electroretinography (ERG), pattern visual evoked potentials (PVEPs) and visual symptoms). Genetic testing was performed using trio whole genome sequencing. Genetic testing confirmed a de-novo pathogenic variant in DNM1, a recurrent heterozygous missense variant, c.709C > T;p.(Arg237Trp). Serial ERG testing at 1, 3, 9 and 12 years old indicated a progressive inner retinal dysfunction affecting both rod and cone synaptic pathways mirroring the abnormalities in the mouse model of dnm1, with normal retinal structure. DNM1 affects retinal synaptic recycling and endocytosis and our findings show likely usefulness of ERG testing in affected individuals. Further work is needed to expand our understanding of how different DNM1 variants affect retinal function.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare recessive genetic conditions characterised by developmental delays and an early onset epilepsy caused by disruptions in the glycosylphosphatidylinositol-anchored biosynthetic pathway. In this study, we identified eight variants in phosphatidyl inositol glycan (PIG) genes from four IGDs families through whole-exome sequencing (WES). The variants included one in PIGA, two in PIGW and five in PIGN, with five being novel variants. Functional analysis confirmed the pathogenicity of the PIGN (c.1117-12C>G) and PIGW (c.1112delT and c.659T>G) variants. According to ACMG/AMP guidelines, four novel variants were classified as pathogenic or likely pathogenic. Families I and III successfully delivered healthy children after prenatal diagnosis. This study identified the pathogenic causes of four IGD pedigrees, expanded the mutation spectrum of PIG genes and provided a theoretical basis for reproductive interventions in such families.