Gene Variants Research Articles

Genetic analysis of a Chinese pedigree affected with Brachydactyly type B1 due to a novel variant of ROR2 gene

To explore the genetic basis for a Chinese pedigree affected with Brachydactyly type B1 (BDB1) through whole exome sequencing (WES). A BDB1 pedigree admitted to the Affiliated Women and Children's Hospital of Qingdao University on June 25, 2021 was selected as the study subject. Clinical data of the pedigree was collected with informed consent. WES was carried out for the proband, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. WES and Sanger sequencing had identified a heterozygous c.2257delT variant in the ROR2 gene of the proband and his affected father, which has conformed to an autosomal dominant pattern of inheritance. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified to be likely pathogenic (PVS1_Strong+PM2 Supporting+PP4). The c.2257delT variant of the ROR2 gene was unreported previously and is strongly correlated with the BDB1-like phenotype in this pedigree. Above finding has enriched the mutational spectrum of the ROR2 gene and facilitated the diagnosis and genetic counseling for this pedigree.

Clinical and genetic analysis of a patient with short stature due to variant of RPL13 gene

To analyze the clinical phenotype and genetic characteristics of a patient with Isidor-Toutain spinal epiphyseal dysplasia (SEMD) due to variant of RPL13 gene. A pregnant woman at 18 weeks of gestation who had presented at Quzhou Maternal and Child Health Care Hospital on January 14, 2023 was selected as the study subject. Whole exome sequencing (WES) was carried out for the patient, and candidate variant was validated by Sanger sequencing and bioinformatic analysis. The woman was 37 years old with extremely short stature (135 cm) and "O" shaped legs. WES revealed that she has harbored a c.548G>C (p.Arg183Pro) missense variant of the RPL13 gene (NM_000977.4). The same variant was not found in her fetus. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4). Isidor-Toutain type SEMD due to variants of the RPL13 gene may have variable expressivity and diverse clinical phenotypes. Above finding has facilitated the differential diagnosis and genetic counseling for this family.

Genetic analysis of a child with Multiple congenital anomalies-hypotonia-seizures syndrome 1 due to variant of PIGN gene

To analyze the clinical phenotype and genetic etiology of a child with Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Clinical data of a 2-year-old boy who had presented at the Affiliated Hospital of Qingdao University in March 2023 for "intermittent limb twitching for 2 years" was collected. Peripheral blood samples were collected from the child and his parents for whole-exome sequencing (WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). The child had manifested with distinctive facial features, limb deformities, hypotonia, motor and intellectual delays, and epileptic seizures. WES revealed that he has harbored compound heterozygous variants of the PIGN gene, namely c.963G>A (p.Q321=) and c.994A>T (p.I332F), which were inherited from his phenotypically normal mother and father, respectively. Based on the ACMG guidelines, the c.963G>A was classified as a pathogenic variant (PVS1+PM2_Supporting+PM3), whilst the c.994A>T was classified as a variant of uncertain significance (PM2_Supporting+PP3). Above discovery has expanded the mutational spectrum of the PIGN gene variants associated with MCAHS1, which may facilitate delineation of its genotype-phenotype correlation.

Association between eNOS gene polymorphisms and the risk of unexplained recurrent spontaneous abortion in Yunnan province, China.

Recurrent spontaneous abortion affects approximately 1-2% of reproductive-age women, with roughly half of RSA cases classified as unexplained recurrent spontaneous abortion (URSA). Genetic polymorphisms in eNOS gene have been shown to have significant implications across various disease processes. Nevertheless, the potential impact of eNOS gene polymorphisms on the susceptibility to URSA in Yunnan population has yet to be explored or documented. This study aims to investigate the potential association between specific variations in the eNOS gene (VNTR 4b/a, -786T > C, and +894G > T) and the risk of URSA in Yunnan population. A total of 243 URSA patients and 241 healthy females are involved in this study. We conducted amplification of the eNOS gene fragment and performed sanger sequencing to detect the specific eNOS gene polymorphisms, including VNTR 4b/a, -786T > C, and +894G > T. Using a multivariate logistic regression model, we evaluate the potential association between eNOS gene polymorphisms (VNTR 4b/a, -786T > C, and +894G > T) and the risk of URSA. Furthermore, serum NO levels were measured in URSA patients. The presence of VNTR 4a, -786C, and +894T alleles was found to be associated with an increased risk of URSA. Additionally, our study revealed a significant association between the G-C-4b haplotype of the investigated eNOS gene polymorphisms and a predisposition to URSA. Notably, these eNOS polymorphisms were shown to reduce serum NO levels in URSA patients. This study provides evidence supporting the association between eNOS gene polymorphisms, VNTR 4b/a, -786T > C, and +894G > T, and the occurrence of URSA in Yunnan Province, China.

Haemophagocytic lymphohistiocytosis caused by GATA2 deficiency: a report on three patients

BackgroundHaemophagocytic lymphohistiocytosis (HLH) is a syndrome that occurs in patients with severe systemic hyperinflammation. GATA binding protein 2 (GATA2) is a transcription factor and key component in haematopoiesis and stem cell biology.Case presentationThree patients with HLH, one with Mycobacterium avium infection, one with Epstein–Barr virus (EBV) infection, and one with Mycobacterium kansasii infection, were all subsequently found to have a defect in the GATA2 gene through genetic testing.ConclusionsGATA2 deficiency syndrome should be considered in patients with myelodysplastic syndrome, nontuberculous mycobacterium infection and HLH. In addition, the GATA2 gene variant may be a genetic defect that could be the cause of the primary HLH. However, further studies are needed to confirm the role of GATA2 pathogenic variants in the pathogenesis of HLH.

Analysis of ADAR gene variants in a Chinese pedigree affected with Dyschromatosis symmetrica hereditaria in conjunct with developmental delay

To explore the clinical characteristics and genetic etiology for a Chinese pedigree affected with Dyschromatosis symmetrica hereditaria (DSH) in conjunct with developmental delay. A child who had presented at the First Affiliated Hospital of Zhengzhou University on May 28 2021 for abnormal skin pigmentation of the extremities and growth retardation for over 2 years was selected as the study subject. Clinical data of the child and his pedigree (11 individuals from three generations) was collected. The child was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing. The child, a two-year-and-seven-month-old male, had hyper- and hypopigmentation on his hands, feet and face, in addition with delayed development. All members of his pedigree had typical presentation of DSH. A heterozygous c.2657G>A variant was found in exon 8 of the ADAR gene in the child, his mother, and elder sister. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as likely pathogenic (PM1+PM2_Supporting+PP1+PP3). The c.2657G>A variant of the ADAR gene probably underlay the DSH in this pedigree.

Novel PHOTOPERIOD-1 gene variants associate with yield-related and root-angle traits in European bread wheat

Key messagePHOTOPERIOD-1 homoeologous gene copies play a pivotal role in regulation of flowering time in wheat. Here, we show that their influence also extends to spike and shoot architecture and even impacts root development.The sequence diversity of three homoeologous copies of the PHOTOPERIOD-1 gene in European winter wheat was analyzed by Oxford Nanopore amplicon-based multiplex sequencing and molecular markers in a panel of 194 cultivars representing breeding progress over the past 5 decades. A strong, consistent association with an average 8% increase in grain yield was observed for the PpdA1-Hap1 haplotype across multiple environments. This haplotype was found to be linked in 51% of cultivars to the 2NS/2AS translocation, originally introduced from Aegilops ventricosa, which leads to an overestimation of its effect. However, even in cultivars without the 2NS/2AS translocation, PpdA1-Hap1 was significantly associated with increased grain yield, kernel per spike and kernel per m2 under optimal growth conditions, conferring a 4% yield advantage compared to haplotype PpdA1-Hap4. In contrast to Ppd-B1 and Ppd-D1, the Ppd-A1 gene exhibits novel structural variations and a high number of SNPs, highlighting the evolutionary changes that have occurred in this region over the course of wheat breeding history. Additionally, cultivars carrying the photoperiod-insensitive Ppd-D1a allele not only exhibit earlier heading, but also deeper roots compared to those with photoperiod-sensitive alleles under German conditions. PCR and KASP assays have been developed that can be effectively employed in marker-assisted breeding programs to introduce these favorable haplotypes.

Diagnostic yield of an inherited retinal disease gene panel in retinopathy of unknown origin

Purpose: Evaluating the presence of class 3, 4 and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO). Methods: Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmological history, complete ophthalmological examination, anti-retinal antibodies and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: non-paraneoplastic autoimmune retinopathy (npAIR), unilateral pigmentary retinopathy (UPR), asymmetrical pigmentary retinopathy (APR) and acute zonal occult outer retinopathy (AZOOR). Results: We included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20 – 68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, 2 also demonstrated class 5 variants in other IRD genes. The remaining 5 patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) npAIR patient in our RUO cohort. When considering the npAIR subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved. Conclusions: Every suspected npAIR patient should benefit from gene panel testing in order not to overlook undiagnosed IRDs. In contrast, UPR, APR and AZOOR subpopulations did not benefit from genetic analysis in this study.

Polymorphic variants of the <i>PPP1R21</i> gene associated with the level of sex hormone-binding globulin and the risk of various stages of breast cancer

Aim. To assess the relationship of polymorphic gene variants associated with the level of sex hormone-binding globulin (SHBG) according to genome-wide association studies (GWAS) with the risk of stage I–II and stage III-IV breast cancer. Materials and methods. A comparative genetic analysis was carried out on samples of patients with breast cancer: 254 patients with stages I–II and 91 with stages III–IV, and 1140 females of the control group. The paper considers 4 single nucleotide substitutions associated with the level of circulating SHBG according to GWAS: g.107546375AG PRMT6 (rs17496332), g.27519736TC GCKR (rs780093), g.48419260TC PPP1R21 (rs10454142), g.98364050TA BAIAP2L1 (rs3779195). Results. Differences in the involvement of polymorphic variants of SHBG candidate genes in the development of stages I–II and III–IV breast cancer were revealed. The rs10454142 TC polymorphic variant in the PPP1R21 gene is associated with the risk of stage I–II breast cancer: women with an allelic variant of this locus have a higher risk of early-stage disease (T/T vs. T/C vs. C/C, odds ratio 1.35, 95% confidence interval 1.05-1.75; p=0.021; ppermutat=0.027). Also, an increase in the number of C alleles in the female genotype increased the risk of stage I–II breast cancer by 17–18% per allele. There were no associations of polymorphic variants of SHBG candidate genes with the risk of severe disease (stage III–IV). The single nucleotide substitution rs10454142 TC in the PPP1R21 gene and the single nucleotide polymorphisms strongly linked to it are functionally significant (located in the regions of enhancers and promoters) in the epithelial and myoepithelial cells of the mammary gland and liver, affect the level of genome methylation, and are associated with the level of GTF2A1L gene expression.

Association of leptin–melanocortin gene polymorphisms with the risk of obesity in northwest Indian population

BackgroundObesity, a multifaceted endocrine issue, is adversely affecting all age groups and is posing a significant public health challenge. The genetic polymorphisms of the melanocortin 4 receptor (MC4R) and leptin (LEP) genes likely contribute to the development of obesity. The present study aimed to explore the effects of MC4R and LEP gene polymorphisms on obesity among the northwest Indian population.MethodsThe present study was conducted among 333 obese cases and 338 non-obese controls (aged 18–50 years). All subjects underwent measurements for anthropometric, physiometric, as well as biochemical parameters. Genotyping for MC4R and LEP gene variants was performed using the polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. However, 10% of the samples for each variant were confirmed using the Sanger sequencing method.ResultsThe polymorphisms of leptin–melanocortin pathway genes (MC4R-LEP) were found to be significantly associated with various obesity-related parameters like waist circumference: p = 0.017, waist-to-height ratio: p = 0.009, total cholesterol: p = 0.0001 and triglycerides: p = 0.0001. Both the LEP gene variants rs2167270 and rs7799039 conferred 2.4- and 2.2-fold risk toward obesity under the recessive genetic model [OR (95% CI) 2.42 (1.44–4.07), p = 0.001; OR (95% CI) 2.26 (1.41–3.60), p = 0.0001, respectively]. All four polymorphisms of the MC4R and LEP genes demonstrated a strong interaction of 82.1% with the lifestyle factor (p = 0.001). The haplotype combinations A–A for rs571312 and rs12970134 conferred twofold risk [OR (95% CI) 2.61 (1.10–6.20), p = 0.028]. However, the combination A–G for rs2167270 and rs7799039 predicted sixfold risk [OR (95% CI) 6.02 (3.39–10.68), p = 0.0001] toward the obesity development in this population.ConclusionOur study revealed a connection between MC4R (rs571312, rs12970134) and LEP (rs2167270, rs7799039) gene variants with obesity, highlighting their prominent role in assessing the risk of obesity among the northwest Indian population.

New in the prevention of undeveloped pregnanc

The problem of non-developing pregnancy (NB) remains relevant due to the rather wide spread of this complication and is due to the search for prognostically significant causes of this pathology, the development of adequate prevention of the detected disorders [1–4]. Polymorphic variants of folate genes lead to excessive accumulation of HC in the blood and hypomethylation of DNA, which contributes to an increase in early miscarriage (the frequency of this pathology is 20–25% of all pregnancies). Carrying out periconceptional prophylaxis with high doses of folic acidreduces the level of free HC in the blood, but this technique is effective only when it begins 3 months before conception and in the early stages of embryo and fetus development (up to 12 weeks). The evaluation of laboratory and clinical data in the course of the study confirmed the effectiveness of the use of folic acid at a dose of 800 mcg in a high risk group for the development of NB (pregnant women with hyperhomocysteinemia (GHZ)) 16 weeks before conception and 12 weeks after conception.

A new Finnish flavor of feline coat coloration, "salmiak," is associated with a 95-kb deletion downstream of the KIT gene.

Cats with a distinctive white hair pattern of unknown molecular cause have been discovered in the Finnish domestic cat population. Based on the unique appearance of these cats, we have named this phenotype salmiak ("salty licorice"). The use of a commercially available panel test to genotype four salmiak-colored cats revealed the absence of all known variants associated with white-haired phenotypic loci: full White (W), Spotting (Ws) and the Birman white Gloves associated (wg) allele of the KIT proto-oncogene (KIT) gene. Whole-genome sequencing on two salmiak-colored cats was conducted to search for candidate causal variants in the KIT gene. Despite a lack of coding variants, visual inspection of the short read alignments revealed a large ~95 kb deletion located ~65 kb downstream of the KIT gene in the salmiak cats. Additional PCR genotyping of 180 domestic cats and three salmiak-colored cats confirmed the homozygous derived variant genotype fully concordant with the salmiak phenotype. We suggest the newly identified variant be designated as wsal for "w salmiak".

Men with metastatic prostate cancer carrying a pathogenic germline variant in breast cancer genes: disclosure of genetic test results to relatives

AbstractSome patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a gene, that is mainly associated with an increased risk of breast cancer in women. If they test positive for such a PV, prostate cancer patients are encouraged to disclose the genetic test result to relatives who are at risk in case the carrier status changes the relatives’ medical care. Our study aimed to investigate how men who learned they carry a PV in BRCA1, BRCA2, PALB2, CHEK2 or ATM disclosed their carrier status to at-risk relatives and to assess the possible psychological burden for the carrier and their perception of the burden for relatives. In total, 23 men with metastatic prostate cancer carrying a PV completed the IRI questionnaire about family communication; 14 also participated in a semi-structured interview. Patients felt highly confident in discussing the genetic test result with relatives. The diagnosis of prostate cancer was experienced as a burden, whereas being informed about genetic testing results did in most cases not add to this burden. Two patients encountered negative experiences with family communication, as they considered the genetic test result to be more urgent than their relatives. This mixed-methods study shows that metastatic prostate cancer patients with a PV in genes mainly associated with increased risk of breast cancer feel well-equipped to communicate about this predisposition in their families. Carriers felt motivated to disclose their genetic test result to relatives. Most of them indicated that the disclosure was not experienced as a psychological burden.

Generation of induced pluripotent stem cell lines from two unrelated patients affected by intellectual disability carrying homozygous variants in SGIP1

Intellectual disability (ID) is a diverse neurodevelopmental condition and almost half of the cases have a genetic etiology. SGIP1 acts as an endocytic protein that influences the signaling of receptors in neuronal systems related to energy homeostasis through its interaction with endophilins. This study focuses on the generation and characterization of induced pluripotent stem cells (iPSC) from two unrelated patients due to a frameshift variant (c.764dupA, NM_032291.4) and a splice donor site variant (c.74 + 1G > A, NM_032291.4) in the SGIP1 gene.

The Role of Cilia and the Complex Genetics of Congenital Heart Disease

Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse chemical mutagenesis screen for mutations causing CHD yielded a preponderance of cilia-related genes, pointing to a central role for cilia in CHD pathogenesis. The genes uncovered by the screen included genes that regulate ciliogenesis and cilia-transduced cell signaling as well as many that mediate endocytic trafficking, a cell process critical for both ciliogenesis and cell signaling. The clinical relevance of these findings is supported by whole-exome sequencing analysis of CHD patients that showed enrichment for pathogenic variants in ciliome genes. Surprisingly, among the ciliome CHD genes recovered were many that encoded direct protein–protein interactors. Assembly of the CHD genes into a protein–protein interaction network yielded a tight interactome that suggested this protein–protein interaction may have functional importance and that its disruption could contribute to the pathogenesis of CHD. In light of these and other findings, we propose that an interactome enriched for ciliome genes may provide the genomic context for the complex genetics of CHD and its often-observed incomplete penetrance and variable expressivity.

Novel WFS1 Variants in Two Moroccan Families with Wolfram Syndrome.

Background: Wolfram syndrome (WFS) is an autosomal recessive disorder that often leads to diabetes, optic atrophy, and sensorineural hearing loss. The aim of this study was to determine the clinical characteristics and the genetic cause of the first two Moroccan families presenting with WFS. Methods: The clinical features of five members of two WFS families were evaluated. Whole-exome sequencing was conducted to explore the underlying genetic cause in the affected patients. Results: Two homozygous variants in the WFS1 gene were identified, each in one of the two families studied: a missense c.1329C>G variant (p.Ser443Arg) and a nonsense mutation c.1113G>A (p.Trp371Ter). These variants affected conserved amino acid residues, segregated well in the two families, and are absent from genetic databases and in controls of Moroccan origin. Bioinformatics analysis classified the two variants as pathogenic by in silico tools and molecular modeling. Conclusion: Our study identified for the first time two variants in Moroccan patients with WFS that extends the mutational spectrum associated with the disease.

The adaptive prowess of the lesser mealworm Alphitobius diaperinus (Coleoptera: Tenebrionidae): Insights from mouthpart morphology and mitogenomic analysis

The lesser mealworm, Alphitobius diaperinus (Panzer, 1797), is a pervasive pest known to infest stored products and poultry facilities worldwide, posing significant challenges for pest management. Understanding its adaptability to diverse environments is crucial for devising effective control strategies. This study investigated adult mouthparts and analyzed the mitogenome of A. diaperinus using specimens obtained from a cat litter box. The examination of mouthparts revealed notable intraspecific variations, suggesting potential adaptations to different ecological conditions. Analysis of the mitogenomes unveiled nucleotide variations in protein-coding genes (PCGs), ribosomal RNA genes (rRNAs), and the control region, with all mutations in PCGs being nonsynonymous, primarily occurring at the second codon positions. Evaluation of Ka/Ks ratios indicated purifying selection acting on the PCGs of A. diaperinus. Phylogenetic analyses consistently placed the newly sequenced sample within the same clade as previously sequenced A. diaperinus samples. The presence of A. diaperinus in cat litter highlights its remarkable adaptability to diverse habitats. Furthermore, intraspecific variation in mouthpart morphology and the mitogenome suggests ongoing adaptations to various food sources and environmental niches. These findings underscore the dynamic nature of A. diaperinus adaptations and emphasize the importance of continued research for effective pest management strategies.

BrBCAT1 mutation resulted in deficiency of epicuticular wax crystal in Chinese cabbage.

BrBCAT1 encoding a branched-chain amino acid aminotransferase was responsible for the glossy trait, which was verified by allelic mutants in Chinese cabbage. The glossy characteristic, thanks to the epicuticular wax crystal deficiency, is an excellent commodity character for leafy vegetables. Herein, two allelic glossy green mutants, wdm11 and wdm12, were isolated from an ethyl methane sulfonate (EMS)-mutagenized population of Chinese cabbage, and the mutant phenotype was recessive inherited. Cryo-SEM detected that epicuticular wax crystal in the mutant leaves was virtually absent. MutMap and Kompetitive allele-specific PCR analyses demonstrated that BraA06g006950.3C (BrBCAT1), homologous to AtBCAT1, encoding a branched-chain amino acid aminotransferase was the candidate gene. A SNP (G to A) on the fourth exon of BrBCAT1 in wdm11 caused the 233rd amino acid to change from glycine (G) to aspartic acid (D). A SNP (G to A) on the second exon of BrBCAT1 in wdm12 led to the 112th amino acid change from glycine (G) to arginine (R). Both of the allelic mutants had genetic structural variation in the candidate gene, which indicated that the mutant phenotype was triggered by the BrBCAT1 mutation. The expression levels of BrBCAT1 and genes related to fatty acid chain extension were decreased significantly in the mutant compared to the wild-type, which might result in epicuticular wax crystal deficiency in the mutants. Our findings proved that the mutation of BrBCAT1 induced the glossy phenotype and provided a valuable gene resource for commodity character improvement in Chinese cabbage.

Distribution of mitochondrial MT-RNR1, MT-TL1, MT-TS1, MT-TK and MT-TE genes variants associated with hearing loss in Southwestern China

BackgroundMaternally inherited hearing loss has been associated with mitochondrial genes, including MT-RNR1, MT-TL1, MT-TS1, MT-TK and MT-TE. Among these genes, MT-RNR1 is known to be a hotspot for pathogenic variants related to aminoglycoside ototoxicity and nonsyndromic hearing loss. However, the frequency and spectrum of variants in these genes, particularly in multi-ethnic hearing loss patients from Southwestern China, are still not fully understood. MethodsIn this study, we enrolled 460 hearing loss patients from various ethnic backgrounds (Han, Yi, Dai, Hani, etc.) in Southwestern China. Next-generation sequencing was used to analyze the mitochondrial MT-RNR1, MT-TL1, MT-TS1, MT-TK and MT-TE genes. Subsequently, bioinformatical methods were employed to evaluate the identified variants. ResultsAmong the patients with hearing loss, we identified 70 variants in MT-RNR1 (78.6 %, 55/70), MT-TL1 (4.3 %, 3/70), MT-TS1 (4.3 %, 3/70), MT-TK (7.1 %, 5/70) and MT-TE (5.7 %, 4/70) genes. We found that 15 variants were associated with hearing loss, including m.1555 A > G and m.1095 T > C. Additionally, we discovered three reported mitochondrial variants (m.676 G > A, m.7465 insC, and m.7474 A > G) newly correlated with hearing loss. Notably, certain pathogenic variants, such as m.1555 A > G, displayed non-consistent distributions among the multi-ethnic patients with hearing loss. Furthermore, the number of variants associated with hearing loss was higher in the Sinitic group (n = 181) and Tibeto-Burman group (n = 215) compared to the Kra-Dai group (n = 38) and Hmong-Mien group (n = 26). ConclusionsThis present study revealed the distribution of mitochondrial variants linked to hearing loss across various ethnic groups in Southwestern China. These data suggest a potential correlation between the distribution of mitochondrial variants associated with hearing loss and ethnic genetic backgrounds.

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson syndrome.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene, which encodes spermine synthase, and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human gene variants and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model, which carries a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts and Sms-null hippocampal cells, indicating that SMS may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS.