A Novel Homozygous Deletion Including Exon 1 of FA2H Gene Causes Spastic Paraplegia-35: Genetic and Lipidomics Analysis of the Patients.

BACKGROUND: Fatty acid 2-hydroxylase (FA2H) is encoded by the FA2H gene, with mutations therein leading to the neurodegenerative condition, spastic paraplegia-35 (SPG35). We aim to elucidate the genetic underpinnings of a nonconsanguineous Chinese family diagnosed with SPG35 by examining the clinical manifestations, scrutinizing genetic variants, and establishing the role of FA2H mutation in lipid metabolism. METHODS: Using next-generation sequencing analysis to identify the pathogenic gene in this pedigree and family cosegregation verification. The use of lipidomics of patient pedigree peripheral blood mononuclear cells further substantiated alterations in lipid metabolism attributable to the FA2H exon 1 deletion. RESULTS: The proband exhibited gait disturbance from age 5 years; he developed further clinical manifestations such as scissor gait and dystonia. His younger sister also presented with a spastic gait from the same age. We identified a homozygous deletion in the region of FA2H exon 1, spanning from chr16:74807867 to chr16: 74810391 in the patients. Lipidomic analysis revealed significant differences in 102 metabolites compared with healthy controls, with 62 metabolites increased and 40 metabolites decreased. We specifically zeroed in on 19 different sphingolipid metabolites, which comprised ceramides, ganglioside, etc., with only three of these sphingolipids previously reported. CONCLUSIONS: This is the first study of lipid metabolism in the blood of patients with SPG35. The results broaden our understanding of the SPG35 gene spectrum, offering insights for future molecular mechanism research and laying groundwork for determining metabolic markers.

Novel maternal duplication of 6p22.3-p25.3 with subtelomeric 6p25.3 deletion: new clinical findings and genotype-phenotype correlations.

BACKGROUND: Copy-number variants (CNVs) drive many neurodevelopmental-related disorders. Although many neurodevelopmental-related CNVs can give rise to widespread phenotypes, it is necessary to identify the major genes contributing to phenotypic presentation. Copy-number variations in chromosome 6, such as independent 6p deletion and 6p duplication, have been reported in several live-born infants and present widespread abnormalities such as intellectual disability, growth deficiency, developmental delay, and multiple dysmorphic facial features. However, a contiguous deletion and duplication in chromosome 6p regions have been reported in only a few cases. CASE PRESENTATION: In this study, we reported the first duplication of chromosome band 6p25.3-p22.3 with deletion of 6p25.3 in a pedigree. This is the first case reported involving CNVs in these chromosomal regions. In this pedigree, we reported a 1-year-old boy with maternal 6p25-pter duplication characterized by chromosome karyotype. Further analysis using CNV-seq revealed a 20.88-Mb duplication at 6p25.3-p22.3 associated with a contiguous 0.66-Mb 6p25.3 deletion. Whole exome sequencing confirmed the deletion/duplication and identified no pathogenic or likely pathogenic variants related with the patient´s phenotype. The proband presented abnormal growth, developmental delay, skeletal dysplasia, hearing loss, and dysmorphic facial features. Additionally, he presented recurrent infection after birth. CNV-seq using the proband´s parental samples showed that the deletion/duplication was inherited from the proband´s mother, who exhibited a similar phenotype to the proband. When compared with other cases, this proband and his mother presented a new clinical finding: forearm bone dysplasia. The major candidate genes contributing to recurrent infection, eye development, hearing loss features, neurodevelopmental development, and congenital bone dysplasia were further discussed. CONCLUSIONS: Our results showed a new clinical finding of a contiguous deletion and duplication in chromosome 6p regions and suggested candidate genes associated with phenotypic features, such as FOXC1, SERPINB6, NRN1, TUBB2A, IRF4, and RIPK1.

[Analysis of a child with X-linked mental retardation due to a de novo variant of DDX3X gene].

OBJECTIVE: To analyze the clinical characteristics and genetic variant of a child featuring X-linked mental retardation. METHODS: Whole exome sequencing and Sanger sequencing were used for the detection of variant and pedigree validation, respectively. Clinical manifestation of patients with DDX3X gene variants were also reviewed. RESULTS: The child was found to harbor a heterozygous NM_001193416.3: c.1332_1333delCT (p.Leu445Serfs*19) variant of the DDX3X gene. The same variant was not found in either of her parents. CONCLUSION: The child was diagnosed with X-linked mental retardation due to variant of the DDX3X gene. Above finding has enriched the spectrum of DDX3X gene variants and provided a basis for clinical diagnosis and prenatal diagnosis for this pedigrees.

Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders.

Objective: According to a recent report, the mutation of transcription factor gene BCL11B is associated with the development of neurodevelopmental disorders and immune deficiency. By analyzing both clinical features and genetic variations, this study aims to reveal the genetic etiology of four patients with neurodevelopmental disorders from two unrelated Chinese pedigrees. Methods: From the 4 cases, the clinical data were collected. The potential pathogenic gene variations were analyzed by means of based-trio whole exome sequencing (Trio-WES) and then validated through Sanger sequencing in their respective pedigrees. Furthermore, both the in vitro minigene assay and the NMD assay were performed to evaluate the impact of splicing and frameshift variants. Results: The 4 patients displayed mild-to-severe intellectual developmental disorder, which was accompanied by speech delay, dysmorphic facies, and serious caries. In addition, the extended phenotype of developmental regression was observed in the proband from Family 1, which has been unreported previously. Molecular analysis was conducted to identify two novel heterozygous variants in the BCL11B gene: a maternal splicing variant c.427 + 1G > A in Family 1 and a de novo frameshift variant c.2461_2462insGAGCCACACCGGCG (p.Glu821Glyfs*28) in Family 2. As revealed by the in vitro minigene assay, the c.427 + 1G > A variant activated a new cryptic splice site. As confirmed by an overexpression assay, there was no significant difference in the level of mRNA and protein expression between the mutate-BCL11B (p.Glu821Glyfs*28) and the wild type. It confirms that p.Glu821Glyfs*28 variant could be an NMD escaping variant. Conclusion: The extended phenotype of BCL11B-related disorders is reported in this study to reveal the clinical and genetic heterogeneity of the disease. The study starts by identifying a splicing variant and a novel frameshift variant of the BCL11B gene, thus confirming its aberrant translation. The findings of this study expand the mutation spectrum of the genetic BCL11B gene, which not only improves the understanding of the associated neurodevelopmental disorders from a clinical perspective but also provides guidance on diagnosis and genetic counseling for patients.

[Analysis of clinical feature and genetic variants in two Chinese pedigrees affected with Bainbridge-Ropers syndrome].

OBJECTIVE: To analyze the clinical features and genetic variants in two unrelated patients with psychomotor retardation and facial abnormalities, and to explore their genotype-phenotype correlation. METHODS: Clinical data and family history of the two pedigrees were collected. Whole exome sequencing (WES) and Sanger sequencing were carried out to detect the potential variants. RESULTS: Both patients had presented with mental and language retardation, along with growth delay and facial anomalies. They were both found to harbor de novo loss-of-function variants in exon 12 of the ASXL3 gene, namely c.3096dup (p.Pro1033Thrfs*2) and c.3253G>T (p.Gly1085*). Neither variant was reported previously. Combined with their clinical features and genetic finding, both patients were diagnosed with Bainbridge-Ropes syndrome due to pathogenic variants of the ASXL3 gene. CONCLUSION: Diagnosis of Bainbridge Ropes syndrome in the two pedigrees has enriched the genotypic and phenotypic spectrum of this disorder and enabled genetic counseling for them.

[Clinical features and genetic analysis of two Chinese patients with Coffin Siris syndrome-1].

OBJECTIVE: To explore the genetic basis for two unrelated patients with global developmental delay and coarse facial features. METHODS: Clinical data and family history of the two pedigrees were collected. Whole exome sequencing and Sanger sequencing were carried out to detect potential variants. RESULTS: The two patients have presented with global developmental delay, coarse facies, muscular hypotonia, congenital heart disease, and pectus excavatum, and were found to harbor two de novo loss-of-function variants of the ARID1B gene, namely c.3586delC (p.Gln1196Serfs*15) and c.4954_4957delACGT (p.Thr1652Glyfs*31). Both variants were unreported previously. CONCLUSION: The nonsense variants of the ARID1B gene probably underlay the etiology in these patients. Above finding has enriched the genotypic and phenotypic spectrum of the disease and provided a basis for prenatal diagnosis.