Neurogenetics最新文献

As a crucial transcription factor, BCL11 transcription factor B gene (BCL11B) is expressed in the cell nucleus, and also widely expressed in the nervous and immune systems. Function of BCL11B varied, mutation of BCL11B gene may involve diverse diseases, such as immunodeficiency 49 (IMD49) and intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities (IDDSFTA). Here we reported a Chinese boy with significant neurodevelopmental delay, whose genetic exam revealed the BCL11B gene mutation. During the 5-year follow-up, no serious immune system defects and infections were found, but some autism spectrum disorders gradually emerged, and the patient was finally diagnosed with IDDSFTA caused by BCL11B mutation. This study is the first to report the phenotypic association between BCL11B gene mutation and moderate hypospadias. Although a previous study has documented the co-occurrence of this gene mutation with hypospadias, the hypospadias in that case was of the mild form. The moderate phenotype presented in this case significantly expands the clinical spectrum of BCL11B-associated disorders.

SPG7-related hereditary spastic paraplegia (SPG7-HSP) is one of the most common forms of autosomal recessive HSP. There is a growing number of reports of affected individuals found to be heterozygous carriers for the recurrent pathogenic coding variants in SPG7, most notably p.Ala510Val, and this has further led to the suggestion of SPG7-HSP having both recessive and dominant forms. Here, we report a proband with pure HSP initially found to carry a heterozygous pathogenic stop-gain variant in SPG7 (NM_ 003119.4:c.1672 A > T; p.Lys558Ter). Subsequent short-read genome sequencing (GS) identified a second, novel deep intronic variant (NM_003119.4:c.987 + 152G > A) in trans, predicted to activate a cryptic splice donor site. RNA sequencing confirmed inclusion of intronic sequence, resulting in a frameshift and premature stop codon (p.Ser330ValfsTer10). This is only the second report of GS uncovering a pathogenic deep intronic variant in SPG7. Our findings highlight that variants only detectable by GS may be an underappreciated disease mechanism and may account for the missing heritability in instances where only a single coding variant is initially identified. Further, critical review of such reports in the literature found no substantial evidence for true autosomal dominant inheritance in SPG7-HSP. These cases most likely represent undetected second variants, alternative molecular diagnoses, or more complex disease mechanisms that have yet to be understood. We recommend the use of GS in individuals with suspected SPG7-HSP carrying only a single pathogenic variant to ensure a complete and accurate molecular diagnosis.

De novo KCNA3 variants cause a Developmental and Epileptic Encephalopathy (DEE). We describe a 14-year-old boy presenting with DEE and carrying a heterozygous de novo KCNA3 (NM_002232.4) variant (c.1433T>A, p.Val478Glu) and an inherited KCNQ3 (NM_004519.3) variant (c.1720C>T, p.Pro574Ser). Human dermal fibroblasts (HDFs) were isolated from the patient and an age-matched control. KCNA3 and KCNQ3 transcript levels were quantified by qRT-PCR, showing in patient-HDFs a reduction of 77% and 40%, respectively (p < 0.0001; p = 0.0002). Western blot confirmed decreased KCNA3 and KCNQ3 protein levels by 50% and 35%, respectively (p < 0.05). The contributing role of both variants supports the rationale for a channel-targeted treatment strategy.

MYCBP2-associated neurodevelopmental disorder is an autosomal dominant genetic disorder, previously described with de novo variants. We present the case of a two-generation review of a proband with a maternally inherited heterozygous pathogenic variant in MYCBP2, c.4409dup (p.Leu1470Phefs*7). Neuropsychology assessment indicated developmental delays with proband's scores falling well below age-level expectations, while proband's mother demonstrated generally intact cognition with evidence of subtle executive inefficiency. Assessment of parental genotype and phenotype can help to anticipate child's developmental trajectory, especially in genetic disorders associated with highly variable expressivity. However information gaps on familial impact of inherited neurodevelopmental disorders across generations remain.

ADK deficiency, an extremely rare inherited metabolic disorder affecting methylation, is likely underdiagnosed as a cause of epilepsy. The limited number of reported cases and variability in presentation, particularly the absence of hypermethioninemia, pose diagnostic challenges. We report an 11-year-9-month-old Indonesian boy with refractory seizures, developmental delay, dysmorphic features, hypotonia, and intellectual disability. Despite normal methionine levels, WES revealed a variant in the ADK gene, confirmed by Sanger sequencing; both parents were heterozygous carriers. Management with multiple antiseizure medications and a methionine-restricted diet reduced seizures, though development remained limited. This case report highlights the first genetically confirmed ADK deficiency case from Indonesia. A concise literature review of reported cases worldwide is also provided to contextualize this atypical phenotype and discuss current diagnostic and therapeutic considerations.

Dystonia-deafness syndrome 1 (DDS1) is a rare disorder caused by the p.(Arg183Trp) heterozygous variant in ACTB. Patients present with congenital/early-onset sensorineural deafness, then childhood/adult-onset generalized dystonia. We describe a 38 y.o patient with additional features, including brain malformations: corpus callosum and vermis hypodysplasia. These novel features expand the clinical spectrum of DDS1, and suggests an overlap with ACTB-related Baraitser-Winter syndrome. Furthermore, we report a limited improvement after Globus Pallidus internus Deep Brain Stimulation (GPi-DBS) contrary to previous publications, bringing a novel message in terms of prognosis.

Allgrove syndrome (AS) is a rare, multisystem, autosomal recessive disorder characterized by the triad of symptoms: achalasia, alacrimia and ACTH-resistant adrenal insufficiency. Various and nonspecific neurological symptoms can also develop over time, "blurring" the typical course of this underdiagnosed condition. The incidence of Allgrove syndrome is unknown. Orphanet database reports fewer than 100 published cases, but according to the literature review, at least 206 patients have already been described. The pathogenic variant p.Ser263Pro is one of the most recurrent aberrations affecting the AAAS gene and has been reported in several families of Slavic origin. We investigated genotype-phenotype correlation in 206 patients with AS described in literature (including two novel Polish siblings carrying a homozygous p.Ser263Pro variant in the AAAS gene) and found that neurological symptoms were significantly more common among carriers of p.Ser263Pro variant (33 out of 34, 97.1%) as compared to other AAAS variant carriers (133 out of 172, 77.3%, p = 0.006). While the incidence of the classical clinical triad of AS was similar and observed in 110 out of 206 AS patients (53.4%) and in 18 out of 34 (52.9%) among p.Ser263Pro variant carriers. Furthermore, our report supports the hypothesis of a founder origin of the p.Ser263Pro variant in AAAS gene in a European Caucasian population. Slavic origin was found in 25 out of 36 reported variant carriers (69.4%) and 17 out of 23 (73.9%) who were homozygous for p.Ser263Pro variant. Summarizing, neurological manifestations of AS predominate in patients carrying a potentially founder p.Ser263Pro variant within the AAAS gene.

Microcephaly primary hereditary (MCPH) is a rare neurodevelopmental disorder characterized by a reduced head circumference and variable severity of intellectual disability, typically inherited in an autosomal recessive pattern. Mutations in over 32 genes have been associated with the etiology of MCPH to date, among which ASPM gene is the most frequently mutated, accounting for approximately 68.8% globally. In Pakistan, particularly within the Pashtun population of Khyber Pakhtunkhwa (KP), ASPM mutations are highly prevalent. In this study, we analysed clinical and genetic features of nine consanguineous MCPH families. Among these, six families revealed recurrent nonsense mutation p.Trp1326*(c.3978G > A), increasing the evidence of it being a founder mutation. In addition to this, genetic analysis of other Pashtun origin families found previously reported nonsense mutation in the same ASPM gene, which include p.Arg3244*(c.9730 C > T), p.Tyr3164*(c.9492T > G), and p.Ser1176*(c.3527 C > G). Clinical assessments of patients revealed microcephaly with mild to severe intellectual disability, impaired interpersonal skills, delayed speech, with no evidence of skeletal, muscular, and major organ abnormalities. Protein modeling and conformation analysis suggested less similarity between wild-type and mutated ASPM proteins, which ranged from 0.24% to 0.68%. Further to the current study, a total of 58 families are known to carry the ASPM p.Trp1326* mutation in the Pashtun Population. These findings emphasize the critical role of ASPM in MCPH pathogenesis, strengthening the evidence of recurrent p.Trp1326* mutation as a founder variant in the Pashtun population. The present study signifies the importance of genetic screening and counselling for effective diagnosis of MCPH in high-risk Pashtun origin Pakistani population.