Clinical Genetics最新文献

Although substantial advancements have been made in genetic testing, several barriers continue to limit patient access, leading to delays in diagnosis, effective treatments, and preventative measures. The NEUROMYODredger-3billion Megaproject End the Diagnostic Odyssey grant offered free whole exome sequencing (WES) to 245 patients with undiagnosed neurodevelopmental or neuromuscular disorders in seven countries: Algeria, Chile, Egypt, France, Mexico, Peru, and Romania. We found pathogenic variants in 79 patients (diagnostic yield 32.24%)-36 neurodevelopmental (43.90%) and 43 neuromuscular (26.38%). Fifty patients harboured variants of uncertain significance (VUS, 20.40%)-14 neurodevelopmental (17.07%) and 36 neuromuscular (22.08%), and 116 patients had negative results (47.34%). NEUROMYODredger helped end the diagnostic odyssey in around 30% of patients, while ongoing functional studies and reanalysis strategies are used in order to reach more diagnoses. In conclusion, a singleton WES approach is valuable in determining the genetic diagnosis of neurodevelopmental and neuromuscular diseases, especially in low and middle-income countries.

Nonsense-mediated mRNA decay (NMD) plays a crucial role in degrading aberrant transcripts with premature termination codons, with the Up-frameshift (UPF) protein family-UPF1, UPF2, and UPF3A/UPF3B-being vital components of this machinery. While several variants in genes encoding UPF2 and UPF3A/3B have been associated with neurodevelopmental disorders, only three germline UPF1 variants have been reported to date. Here, we report a male patient with a de novo missense variant, p.(Ala526Thr), in a highly conserved helicase motif of UPF1. The patient presented with moderate intellectual disability (ID), atypical autism, attention deficit hyperactivity disorder (ADHD), and behavioral disturbances. The common features observed among the four patients with UPF1 variants are moderate to severe ID and developmental delays in motor and verbal skills. A comparison across the disorders related to the UPF genes suggests that neurodevelopmental delay, including ID and impaired verbal skills, is a common feature, and these disorders may collectively be referred to as UPF-related neurodevelopmental disorders (NDDs). ADHD, autism, seizures, hypotonia, and non-specific dysmorphic features are also reported in some patients, suggesting that these disorders can be classified as non-specific intellectual disability syndromes. However, further studies are necessary to elucidate genotype-phenotype correlations and the molecular mechanisms underlying these rare disorders, particularly those related to UPF1.

Kohlschütter-Tönz Syndrome (KTS) is an ultra-rare autosomal recessive disorder, characterized by a clinical triad: infantile-onset epilepsy, global developmental delay, and amelogenesis imperfecta. KTS is caused by pathogenic variants in ROGDI, encoding a leucine zipper protein of unknown function. Our study characterizes a novel homozygous ROGDI variant (NM_024589.3:c.646-2A>G) identified in a Tunisian family case with KTS, renal tubular acidosis, and hyperammonemia. This variant disrupts a canonical acceptor splice site (ASS) in intron 8. Reverse-transcriptase polymerase chain reaction and targeted long-read cDNA sequencing, identified only abnormal transcripts secondary to the ROGDI ASS variant in the proband. Complex splicing events were detected including exon 9 skipping, cryptic ASS activation leading to 13-bp deletion in exon 9, and retention of intron 8 or both intron 8 and 9. These alterations were all predicted to result in nonsense mediated decay and ROGDI loss of function. By integrating complementary techniques, our study unveiled fundamental mechanisms underlying complex splice alterations, providing insights that may guide future therapeutic strategies in KTS.

The mTOR cascade is a critical player in the pathogenesis of focal epilepsies and cortical malformations, collectively referred to as mTORopathies. The Ras homolog enriched in brain (RHEB) gene is a member of the RAS-family GTPases and a potent activator of the mechanistic target of rapamycin complex (mTORC1). Brain somatic variants in the RHEB gene have been described in patients affected by focal cortical dysplasia and hemimegalencephaly abnormalities. Conversely, germline genetic variants in the RHEB gene have been poorly reported in patients with neurodevelopmental disorders. This study describes the phenotype of a patient with global developmental delay and epilepsy carrying a novel germline de novo heterozygous missense variant (c.71 T>C; p.Ile24Thr) in the RHEB gene. Previously reported patients are reviewed and compared to the case reported here, expanding the genotype and phenotype spectrum of mTORopathies.

SPTAN1 mutations have been reported in association with autosomal dominant early infantile epileptic encephalopathy 5. Individuals present with early-onset seizures and profound intellectual disability. Recent reports suggest a wider spectrum with later-onset seizures and milder developmental delay. Here we describe two patients with loss-of-function variants in SPTAN1. One patient has ataxia and mild intellectual disability stemming from a de novo homozygous p.(Gln1448Pro) variant associated with uniparental disomy 9. The second patient, carrying a heterozygous p.(Asn1839del) allele, exhibits more substantial motor issues, developmental delay, and seizures. Ectopically expressed wild-type or variant-containing forms of sptan1 in zebrafish indicate both variants create loss-of-function alleles, with the p.(Gln1448Pro) likely being hypomorphic. This conclusion is supported by reduced protein abundance and localization of Sptan1 variants in axons of developing embryos. Further, unlike wild-type sptan1, analysis of the p.(Gln1448Pro) variant showed it failed to restore voltage-gated sodium channel localization in sptan1-null axons. Additional behavioral analyses show supplementation with the amino acid D-aspartate improved motility in sptan1-null zebrafish, supporting its use for α-II spectrin-associated motor dysfunction.

Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) is a rare autosomal recessive disorder characterized by malformation or absence of the corpus callosum, accompanied by progressive peripheral nerve degeneration. ACCPN is associated with mutations in the SLC12A6 gene, encoding the potassium-chloride cotransporter (also termed KCC3), which plays a crucial role in neuronal ion homeostasis. In this study, we report a novel homozygous missense variant (c.1634A>G, p.H371R) in SLC12A6, identified through exome sequencing in a male proband presenting with ACCPN symptoms, including developmental delay, hypotonia, epileptic seizures, and corpus callosal dysgenesis. The proband's MRI findings revealed additional neurodevelopmental abnormalities such as hippocampal malformation. Functional analysis showed that while the mutant SLC12A6 transcript and protein levels were comparable to wild type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function. This mislocalization caused an imbalance in potassium and chloride ion levels in the proband's cells. Bioinformatics tools predicted the pathogenicity of the p.H371R mutation, and structural modeling revealed a destabilization effect. Elevated levels of cellular senescence markers, p16 and p21, were detected, indicating that ion dysregulation due to SLC12A6-p.H371R mislocalization contributed to cellular stress. This study provides novel insights into the pathogenic mechanism of ACCPN, highlighting the importance of mutant SLC12A6 mislocalization and ion homeostasis in disease progression. The identification of the p.H371R mutation adds to the spectrum of SLC12A6 mutations linked to ACCPN and underscores the potential for targeted therapeutic strategies.

Congenital tufting enteropathy (CTE) is a rare autosomal recessive inherited disorder caused by mutations in the epithelial cell adhesion molecule (EpCAM) gene, characterized by severe diarrhea and growth failure. Between December 2017 and December 2023, eight patients diagnosed with CTE at our hospital were retrospectively analyzed for their clinical and genetic features, alongside a comprehensive literature review. All patients presented with severe malnutrition and growth failure upon admission. Parenteral nutrition (PN) with high caloric intake was required for all patients to achieve growth catch-up. A total of 142 patients with EpCAM mutations were reviewed, including 137 previously reported cases and five newly identified patients described in this study. Among the 114 CTE patients with detailed treatment information, 108 patients received PN therapy, with six patients successfully weaned off PN. Additionally, 19 patients underwent intestinal transplantation (IT). Outcome analysis revealed that 30 patients (27.3%) died, including five post-IT deaths. A total of 68 EpCAM mutations were identified, with most located in exon 3. The most frequently reported variant was c.499dup C. In this study, four novel mutations were detected in our patients. This study provides a comprehensive overview of the clinical and genetic characteristics of CTE, enhancing the understanding of its phenotype and genotype, particularly in Asian patients.

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.