Journal of Human Genetics最新文献

Lafora disease (LD) is a severe autosomal recessive disease, which usually presents as seizure and myoclonus, followed by behavioral changes, dysarthria, intellectual decline, and finally progressed to dementia and a vegetative state. The main cause of LD is the loss-of-function mutations in EPM2A and NHLRC1 that encode laforin and malin, respectively. Targeted genetic testing is the gold standard to confirm the diagnosis of LD. To describe the pathogenic role of biallelic EPM2A intronic mutations carried by patients in a family diagnosed as LD. Here, we present clinical findings in a patient presenting with epileptic seizures and Lafora bodies in muscle biopsy. Long-read DNA and RNA sequencing were performed to identify the causative mutation. Western blot and qPCR confirmed the pathogenic role of biallelic EPM2A intronic mutations. Genetic testing identified two intronic mutations in EPM2A which caused aberrant mRNA splicing. c.301+1 G > A in EPM2A caused aberrant splicing at donor site and resulted in intron retention in transcript NM_005670.4, while c.476+14860 C > A caused aberrant splicing in transcript NM_001368129.2 and NM_001368132.1. Our findings expand the spectrum of variants in LD disease, additionally providing evidence linking non-coding regulatory regions mutations to LD disease.

Variants in HSPB8 are predominantly associated with peripheral neuropathies, but their occurrence in myopathies remains exceedingly rare. The genetic and clinical spectrum of HSPB8-related myopathy is not yet complete. Herein, we not only described the first Chinese case of HSPB8-related myopathy characterized by a novel heterozygous frameshift variant (c.576_579delinsCAG, p.Glu192Aspfs*55) in the C-terminal region of HSPB8, but also established the first association between this specific HSPB8 variant and pediatric-onset axial and limb-girdle myopathy. Muscle pathology revealed myofibrillar myopathy features and the novel pathological findings of inflammatory responses and vacuoles with sarcolemmal features pathology. Functional studies demonstrated significant colocalization of HSPB8 with autophagy markers and upregulation of autophagy-related proteins, which suggested that autophagic dysregulation may contribute to the pathological process of this disease. Furthermore, comprehensive bioinformatics analysis and molecular dynamics simulations revealed an increased propensity for aggregation, as well as altered structural and biochemical properties in the mutant HSPB8. Our study highlights the importance of considering HSPB8 mutations in early-onset axial and limb-girdle myopathy, expanding the genetic and phenotypic spectrum of the disease. Notably, our results underscore the critical role of autophagy dysregulation and aberrant protein aggregation in the pathogenesis, providing novel insights into potential therapeutic targets.

Asthenospermia is a type of sperm that has malformed sperm with movement disorders that lead to male infertility. DNAH9 is a member of the dynein family and a central part of the outer dynein arm of cilia and flagella. DNAH9 gene defects are associated with primary ciliary dyskinesia and ultrastructural abnormalities in ciliary axial ultrastructure. However, the role of DNAH9 in sperm motility remains unclear, prompting us to investigate its function in spermatozoa. Familial Sanger sequencing showed that sterile males carried homozygous DNAH9 variants (c. 12218A>C, p. N4073T) and compound heterozygous variants (c.8617G>A, p.V2873M; c.11742A>T, p.E3914D), respectively. Transmission electron microscopy revealed these variants resulted in a significant lack of outer dynein arms in the cross-sectional view of the axoneme in both patients. Immunofluorescence results showed that these variants can lead to decline in DNAH9 protein expression, which led to the dysfunction of flagellar ultrastructure-related proteins, including DNAI1, DNAH1 and DNAH10. In conclusion, we identified novel biallelic variants in DNAH9 that likely bring about sharply decreased motility of spermatozoa in the two patients with asthenospermia. Our findings will widen the variant spectrum of known DNAH9 variants involving asthenospermia and further offer more proofs for genetic counseling and diagnosis.

Regions of homozygosity (ROH) increase the risk of recessive disorders, and guidelines recommend reporting of excessive ROH in prenatal testing. However, ROH are common in populations that practice endogamy or consanguinity, and cutoffs for reporting ROH in such populations may not be evidence-based. We reviewed prenatal testing results (based on cytogenetic microarrays) from 2191 pregnancies in the Jewish and non-Jewish populations of Northern Israel and estimated the prevalence of ROH according to self-reported ethnicity and parental relationships. The proportion of the genome in ROH, ROH rate, was higher in non-Jews [Mean (SD) = 2.91% (3.92%); max = 25.54%; N = 689] than in Jews [Mean (SD) = 0.81% (0.49%); max = 3.93%; N = 1502]. In the non-Jewish populations, consanguineous marriages had the highest ROH rates [Mean (SD) = 7.14% (4.55%), N = 217], followed by endogamous [Mean (SD) = 1.13% (1.09%), N = 283] and non-endogamous [Mean (SD) = 0.69%(0. 56%), N = 189] marriages. ROH rates were greater than 5%, the ACMG-recommended cutoff, in 149/689 (21.63%) of the non-Jewish samples. Within the Jewish populations, the rates were similar between Ashkenazi, North African, and Middle Eastern Jews, but were higher for six consanguineous unions [Mean (SD) = 2.38% (1.23%)] and when spouses belonged to the same sub-population. Given the high ROH rates we observed in some subjects, we suggest that assessing the risk for recessive conditions in consanguineous/endogamous populations should be done before the first pregnancy, through genetic counseling and sequencing. Such an approach will: (1) identify couples who are at risk and counsel them on reproductive options; and (2) avoid the stress that couples who are not at risk may experience due to a prenatal ROH report.

FAM111A (family with sequence similarity 111 member A) is a serine protease and removes covalent DNA-protein cross-links during DNA replication. Heterozygous gain-of-function variants in FAM111A cause skeletal dysplasias, such as the perinatal lethal osteocraniostenosis and the milder Kenny-Caffey syndrome (KCS). We report two siblings born to consanguineous parents with dysmorphic craniofacial features, postnatal growth retardation, ophthalmologic manifestations, hair and nail anomalies, and skeletal abnormalities such as thickened cortex and stenosis of the medullary cavity of the long bones suggestive of KCS. Using exome sequencing, a homozygous synonymous FAM111A variant, NM_001312909.2:c.81 G > A; p.Pro27=, that affects the last base of the exon and is predicted to alter FAM111A pre-mRNA splicing, was identified in both siblings. We identified aberrantly spliced FAM111A transcripts, reduced FAM111A mRNA levels, and near-complete absence of FAM111A protein in fibroblasts of both patients. After treatment of patient and control fibroblasts with different concentrations of camptothecin that induces covalent DNA-protein cross-links, we observed a tendency towards a reduced proportion of metabolically active cells in patient compared to control fibroblasts. However, under these culture conditions, we did not find consistent and statistically significant differences in cell cycle progression and apoptotic cell death between patient and control cells. Our findings show that FAM111A deficiency underlies an autosomal recessive form of FAM111A-related KCS. Based on our results and published data, we hypothesize that loss of FAM111A and FAM111A protease hyperactivity, as observed for gain-of-function patient-variant proteins, may converge on a similar pathomechanism underlying skeletal dysplasias.

Hypomyelinating leukodystrophy-5 (HLD5) is a rare autosomal recessive hypomyelination disorder characterized by congenital cataract, progressive neurologic impairment, and myelin deficiency in the central and peripheral nervous system, caused by mutations in the HYCC1 gene. Here we report a 23-year-old girl with HLD5 from unrelated families. Molecular analysis was performed using sequence screening of the HYCC1 gene. In addition, in silico prediction tools and molecular investigation were used to predict the structural effect of the mutations. Results showed a novel compound heterozygous mutation in the HYCC1 gene. Moreover, in silico tools and 3D structural modeling revealed that c.521C > A (p.Ala174Glu) and c.652C > G (p.Gln218Glu) mutations could affect the structure, stability, and conformational analyses in the N-ter domain of the Hyccin protein. We also, we compared the phenotype of our patient with those of previously reported cases with HLD5 syndrome and our findings indicate the absence of reliable genotype-phenotype correlations. To the best of our knowledge, this is the first report describing a Tunisian HLD5 patient with compound heterozygous mutations (c.521C > A (p.Ala174Glu) and c.652C > G (p.Gln218Glu)) in HYCC1 gene.

Biallelic loss of function variants in ESAM (endothelial cell adhesion molecule) have recently been reported in 14 individuals (9 families) presenting with prenatal intracranial hemorrhage. Here, we describe four patients from two unrelated families in whom three of them presented with variable onset encephalopathy and seizures while one only displayed profound delay without seizures. Brain MRI showed variable onset intracranial hemorrhage that evolved to hydrocephalus in 3 patients, whereas hemosiderin deposits, white matter volume loss, and porencephalic cysts were noted in one patient. Unlike the majority of described cases, the youngest brother of the first family did not show microcephaly and failure to thrive. Exome sequencing identified two novel homozygous ESAM variants. A splice variant (c.731-2A>G) was identified in one family which was confirmed by investigating the patient's mRNA to result in exon skipping and early protein truncation. In addition, a missense variant (c.561G>C; p.Trp187Cys) was identified in the other family, which is the first disease causing missense variant to be described in patients with ESAM deficient phenotype. In addition, a maternally inherited pathogenic MC4R variant (c.811T>C; p.Cys271 Arg) was also identified in the youngest brother of the first family. Variants in the MC4R gene are associated with a non-syndromic form of obesity that could explain the unusual macrocephaly and obesity. Our work establishes ESAM as a tight junction gene that can present with variable neuroradiological and clinical phenotypes when mutated. Moreover, it refines the phenotype of this ultrarare syndrome and extends the number and type of variants described to date.

CEP55 encodes centrosomal protein 55 kDa, which plays a crucial role in mitosis, particularly cytokinesis. Biallelic CEP55 variants cause MARCH syndrome (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly). Here, we describe a Japanese family with two affected siblings harboring novel compound heterozygous CEP55 variants, NM_001127182: c.[1357 C > T];[1358 G > A] p.[(Arg453Cys)];[(Arg453His)]. Both presented clinically with typical lethal MARCH syndrome. Although a combination of missense and nonsense variants has been reported previously, this is the first report of biallelic missense CEP55 variants. These variants biallelically affected the same amino acid, Arg453, in the last 40 amino acids of CEP55. These residues are functionally important for CEP55 localization to the midbody during cell division, and may be associated with severe clinical outcomes. More cases of pathogenic CEP55 variants are needed to establish the genotype-phenotype correlation.

FBXW7 (F-box and WD-repeat domain-containing 7) is a tumor suppressor gene, and its germline variants have been causally linked to Wilms tumors. Furthermore, germline variants of FBXW7 have also been implicated in a neurodevelopmental syndrome. However, little is known regarding the occurrence of Wilms tumor in patients with FBXW7-related neurodevelopmental syndrome. We identified a novel constitutional pathogenic variant of FBXW7 in a patient with intellectual disability, who also developed Wilms tumor. The variant was derived from his apparently normal mother, and was also detected in his sister who exhibited developmental delay. Furthermore, we detected a somatic nonsense variant on the paternal allele of FBXW7 in the tumor DNA. These results suggest that the development of Wilms tumor along with FBXW7-related neurodevelopmental syndrome follows the two-hit model, which needs to be validated to establish appropriate follow-up management and tumor surveillance.

Mainland Japanese have been recognized as having dual ancestry, originating from indigenous Jomon people and immigrants from continental East Eurasia. Although migration from the continent to the Japanese Archipelago continued from the Yayoi to the Kofun period, our understanding of these immigrants, particularly their origins, remains insufficient due to the lack of high-quality genome samples from the Yayoi period, complicating predictions about the admixture process. To address this, we sequenced the whole nuclear genome of a Yayoi individual from the Doigahama site in Yamaguchi prefecture, Japan. A comprehensive population genetic analysis of the Doigahama Yayoi individual, along with ancient and modern populations in East Asia and Northeastern Eurasia, revealed that the Doigahama Yayoi individual, similar to Kofun individuals and modern Mainland Japanese, had three distinct genetic ancestries: Jomon-related, East Asian-related, and Northeastern Siberian-related. Among non-Japanese populations, the Korean population, possessing both East Asian-related and Northeastern Siberian-related ancestries, exhibited the highest degree of genetic similarity to the Doigahama Yayoi individual. The analysis of admixture modeling for Yayoi individuals, Kofun individuals, and modern Japanese respectively supported a two-way admixture model assuming Jomon-related and Korean-related ancestries. These results suggest that between the Yayoi and Kofun periods, the majority of immigrants to the Japanese Archipelago originated primarily from the Korean Peninsula.