Molecular Etiology of Hearing Impairment in Inner Mongolia: mutations in SLC26A4 gene and relevant phenotype analysis

<p>Abstract</p> <p>Background</p> <p>The molecular etiology of hearing impairment in Chinese has not been thoroughly investigated. Study of <it>GJB2 </it>gene revealed that 30.4% of the patients with hearing loss in Inner Mongolia carried <it>GJB2 </it>mutations. The <it>SLC26A4 </it>gene mutations and relevant phenotype are analyzed in this study.</p> <p>Methods</p> <p>One hundred and thirty-five deaf patients were included. The coding exons of <it>SLC26A4 </it>gene were sequence analyzed in 111 patients, not including 22 patients carrying bi-allelic <it>GJB2 </it>mutations or one patient carrying a known <it>GJB2 </it>dominant mutation as well as one patient with <it>mtDNA </it>1555A>G mutation. All patients with <it>SLC26A4 </it>mutations or variants were subjected to high resolution temporal bone CT scan and those with confirmed enlarged vestibular aqueduct and/or other inner ear malformation were then given further ultrasound scan of thyroid and thyroid hormone assays.</p> <p>Results</p> <p>Twenty-six patients (19.26%, 26/135) were found carrying <it>SLC26A4 </it>mutation. Among them, 17 patients with bi-allelic <it>SLC26A4 </it>mutations were all confirmed to have EVA or other inner ear malformation by CT scan. Nine patients were heterozygous for one <it>SLC26A4 </it>mutation, including 3 confirmed to be EVA or EVA and Mondini dysplasia by CT scan. The most common mutation, IVS7-2A>G, accounted for 58.14% (25/43) of all <it>SLC26A4 </it>mutant alleles. The shape and function of thyroid were confirmed to be normal by thyroid ultrasound scan and thyroid hormone assays in 19 of the 20 patients with EVA or other inner ear malformation except one who had cystoid change in the right side of thyroid. No Pendred syndrome was diagnosed.</p> <p>Conclusion</p> <p>In Inner Mongolia, China, mutations in <it>SLC26A4 </it>gene account for about 12.6% (17/135) of the patients with hearing loss. Together with <it>GJB2 </it>(23/135), <it>SLC26A4 </it>are the two most commonly mutated genes causing deafness in this region. Pendred syndrome is not detected in this deaf population. We established a new strategy that detects <it>SLC26A4 </it>mutations prior to the temporal bone CT scan to find EVA and inner ear malformation patients. This model has a unique advantage in epidemiologic study of large deaf population.</p

Comprehensive molecular etiology analysis of nonsyndromic hearing impairment from typical areas in China

<p>Abstract</p> <p>Background</p> <p>Every year, 30,000 babies are born with congenital hearing impairment in China. The molecular etiology of hearing impairment in the Chinese population has not been investigated thoroughly. To provide appropriate genetic testing and counseling to families, we performed a comprehensive investigation of the molecular etiology of nonsyndromic deafness in two typical areas from northern and southern China.</p> <p>Methods</p> <p>A total of 284 unrelated school children with hearing loss who attended special education schools in China were enrolled in this study, 134 from Chifeng City in Inner Mongolia and the remaining 150 from Nangtong City in JiangSu Province. Screening was performed for <it>GJB2</it>, <it>GJB3</it>, <it>GJB6</it>, <it>SLC26A4</it>, <it>12S rRNA</it>, <it>and tRNA</it>^{<it>ser</it>(<it>UCN</it>)}genes in this population. All patients with <it>SLC26A4 </it>mutations or variants were subjected to high-resolution temporal bone CT scan to verify the enlarged vestibular aqueduct.</p> <p>Results</p> <p>Mutations in the <it>GJB2 </it>gene accounted for 18.31% of the patients with nonsyndromic hearing loss, 1555A>G mutation in mitochondrial DNA accounted for 1.76%, and <it>SLC26A4 </it>mutations accounted for 13.73%. Almost 50% of the patients with nonsyndromic hearing loss in these typical Chinese areas carried <it>GJB2 </it>or <it>SLC26A4 </it>mutations. No significant differences in mutation spectrum or prevalence of <it>GJB2 </it>and <it>SLC26A4 </it>were found between the two areas.</p> <p>Conclusion</p> <p>In this Chinese population, 54.93% of cases with hearing loss were related to genetic factors. The <it>GJB2 </it>gene accounted for the etiology in about 18.31% of the patients with hearing loss, <it>SLC26A4 </it>accounted for about 13.73%, and <it>mtDNA </it>1555A>G mutation accounted for 1.76%. Mutations in <it>GJB3, GJB6</it>, and <it>mtDNA tRNA</it>^{<it>ser</it>(<it>UCN</it>)}were not common in this Chinese cohort. Conventionally, screening is performed for <it>GJB2</it>, <it>SLC26A4</it>, and mitochondrial <it>12S rRNA </it>in the Chinese deaf population.</p

Prevalence of the GJB2 IVS1+1G >A mutation in Chinese hearing loss patients with monoallelic pathogenic mutation in the coding region of GJB2

<p>Abstract</p> <p>Background</p> <p>Mutations in the GJB2 gene are the most common cause of nonsyndromic recessive hearing loss in China. In about 6% of Chinese patients with severe to profound sensorineural hearing impairment, only monoallelic <it>GJB2 </it>mutations known to be either recessive or of unclear pathogenicity have been identified. This paper reports the prevalence of the <it>GJB2 </it>IVS1+1G>A mutation in a population of Chinese hearing loss patients with monoallelic pathogenic mutation in the coding region of <it>GJB2</it>.</p> <p>Methods</p> <p>Two hundred and twelve patients, screened from 7133 cases of nonsyndromic hearing loss in China, with monoallelic mutation (mainly frameshift and nonsense mutation) in the coding region of <it>GJB2 </it>were examined for the <it>GJB2 </it>IVS1+1G>A mutation and mutations in the promoter region of this gene. Two hundred and sixty-two nonsyndromic hearing loss patients without <it>GJB2 </it>mutation and 105 controls with normal hearing were also tested for the <it>GJB2 </it>IVS1+1G>A mutation by sequencing.</p> <p>Results</p> <p>Four patients with monoallelic mutation in the coding region of <it>GJB2 </it>were found carrying the <it>GJB2 </it>IVS1+1G>A mutation on the opposite allele. One patient with the <it>GJB2 </it>c.235delC mutation carried one variant, -3175 C>T, in exon 1 of <it>GJB2</it>. Neither <it>GJB2 </it>IVS1+1G>A mutation nor any variant in exon 1 of <it>GJB2 </it>was found in the 262 nonsyndromic hearing loss patients without <it>GJB2 </it>mutation or in the 105 normal hearing controls.</p> <p>Conclusion</p> <p>Testing for the <it>GJB2 </it>IVS 1+1 G to A mutation explained deafness in 1.89% of Chinese <it>GJB2 </it>monoallelic patients, and it should be included in routine testing of patients with <it>GJB2 </it>monoallelic pathogenic mutation.</p

Extremely discrepant mutation spectrum of SLC26A4 between Chinese patients with isolated Mondini deformity and enlarged vestibular aqueduct

<p>Abstract</p> <p>Background</p> <p>Mutations in <it>SLC26A4 </it>cause Pendred syndrome (hearing loss with goiter) or DFNB4 (non-syndromic hearing loss with inner ear malformation, such as enlarged vestibular aqueduct or Mondini deformity). The relationship between mutations in <it>SLC26A4 </it>and Mondini deformity without enlarged vestibular aqueduct has not been studied in any Chinese deaf population. The purpose of this study was to assess whether mutations in the <it>SLC26A4 </it>gene cause Mondini deformity without an enlarged vestibular aqueduct (isolated Mondini deformity) in a Chinese population.</p> <p>Methods</p> <p>In total, 144 patients with sensorineural hearing loss were included and subjected to high-resolution temporal bone CT. Among them, 28 patients with isolated Mondini dysplasia (MD group), 50 patients with enlarged vestibular aqueduct with Mondini dysplasia (EVA with MD group), 50 patients with enlarged vestibular aqueduct without Mondini dysplasia (EVA group), and 16 patients with other types of inner ear malformations (IEM group) were identified. The coding exons of <it>SLC26A4 </it>were analyzed in all subjects.</p> <p>Results</p> <p>DNA sequence analysis of <it>SLC26A4 </it>was performed in all 144 patients. In the different groups, the detection rate of the <it>SLC26A4 </it>mutation differed. In the isolated MD group, only one single allelic mutation in <it>SLC26A4 </it>was found in one patient (1/28, 3.6%). In the EVA with MD group, biallelic and monoallelic <it>SLC26A4 </it>mutations were identified in 46 patients (46/50, 92.0%) and three patients (3/50, 6.0%), respectively. Also, in the EVA group, biallelic and monoallelic <it>SLC26A4 </it>mutations were identified in 46 patients (46/50, 92.0%) and three patients (3/50, 6.0%), respectively. These percentages were identical to those in the EVA plus MD group. Only two patients carried monoallelic mutations of the <it>SLC26A4 </it>gene in the IEM group (2/16, 12.5%). There were significant differences in the frequency of <it>SLC26A4 </it>mutation among the groups (P < 0.001). The detection rate of <it>SLC26A4 </it>mutation in the isolated MD group was significantly lower than in the EVA group (with or without MD; P < 0.001), and there was no significant difference in the detection rate of <it>SLC26A4 </it>between the MD group and IEM group (P > 0.5).</p> <p>Conclusion</p> <p>Although mutations in the <it>SLC26A4 </it>gene were frequently found in Chinese EVA patients with and without MD, there was no evidence to show a relationship between isolated MD and the <it>SLC26A4 </it>gene in the Chinese population examined. Hearing impairment in patients with isolated MD may be caused by factors other than mutations in the <it>SLC26A4 </it>gene.</p

CLIP-Driven Universal Model for Organ Segmentation and Tumor Detection

An increasing number of public datasets have shown a marked impact on automated organ segmentation and tumor detection. However, due to the small size and partially labeled problem of each dataset, as well as a limited investigation of diverse types of tumors, the resulting models are often limited to segmenting specific organs/tumors and ignore the semantics of anatomical structures, nor can they be extended to novel domains. To address these issues, we propose the CLIP-Driven Universal Model, which incorporates text embedding learned from Contrastive Language-Image Pre-training (CLIP) to segmentation models. This CLIP-based label encoding captures anatomical relationships, enabling the model to learn a structured feature embedding and segment 25 organs and 6 types of tumors. The proposed model is developed from an assembly of 14 datasets, using a total of 3,410 CT scans for training and then evaluated on 6,162 external CT scans from 3 additional datasets. We rank first on the Medical Segmentation Decathlon (MSD) public leaderboard and achieve state-of-the-art results on Beyond The Cranial Vault (BTCV). Additionally, the Universal Model is computationally more efficient (6x faster) compared with dataset-specific models, generalized better to CT scans from varying sites, and shows stronger transfer learning performance on novel tasks.Comment: Rank first in Medical Segmentation Decathlon (MSD) Competitio

Variation in Contents of Iodine Species in Kelp during Blanching-Salting Process

In this study, the contents of four iodine forms, including iodide ion (I−), iodate (IO3−), mono-iodotyrosine (MIT) and diiodotyrosine (DIT), were determined in the blanching water, rinsing water, saline water and processed kelp to study the dissolution patterns of iodine forms during the blanching, rinsing and salting of kelp. The I− contents in fresh, blanched, primarily rinsed and secondarily rinsed kelp were 1 689.41–8 753.24 mg/kg, and the contents of IO3− ranged from 42.67 to 442.00 mg/kg. The contents of MIT and DIT ranged from 698.22 to 861.90 mg/kg and 123.97 to 158.67 mg/kg, respectively. During the blanching process, the dissolution rates of I−, MIT and DIT were the highest, which were (64.38 ± 2.99)%, (19.35 ± 0.97)% and (6.55 ± 0.53)%, respectively. With increasing kelp addition, the contents of I−, MIT and DIT in the blanching, rinsing and saline water first increased and then leveled off, and the content of IO3− in all waters showed a monotonously increasing trend. With increasing number of kelp rinsed, the dissolution rate of I− decreased first and then basically remained unchanged. Compared with fresh kelp, the dissolution rate of I− in the first rinsed kelp decreased by (80.72 ± 2.66)%, and iodine was released into water mainly in the form of I−, with the maximum release being recorded during the blanching process

Identification of two novel and one rare mutation in DYRK1A and prenatal diagnoses in three Chinese families with intellectual Disability-7

Background and purpose: Intellectual disability-7 (MRD7) is a subtype disorder of intellectual disability (MRD) involving feeding difficulties, hypoactivity, and febrile seizures at an age of early onset, then progressive intellectual and physical development deterioration. We purposed to identify the underlying causative genetic factors of three individuals in each Chinese family who presented with symptoms of intellectual disability and facial dysmorphic features. We provided prenatal diagnosis for the three families and genetic counseling for the prevention of this disease.Methods: We collected retrospective clinical diagnostic evidence for the three probands in our study, which included magnetic resonance imaging (MRI), computerized tomography (CT), electroencephalogram (EEG), and intelligence tests for the three probands in our study. Genetic investigation of the probands and their next of kin was performed by Trio-whole exome sequencing (WES). Sanger sequencing or quantitative PCR technologies were then used as the next step to verify the variants confirmed with Trio-WES for the three families. Moreover, we performed amniocentesis to explore the state of the three pathogenic variants in the fetuses by prenatal molecular genetic diagnosis at an appropriate gestational period for the three families.Results: The three probands and one fetus were clinically diagnosed with microcephaly and exhibited intellectual developmental disability, postnatal feeding difficulties, and facial dysmorphic features. Combining probands’ clinical manifestations, Trio-WES uncovered the three heterozygous variants in DYRK1A: a novel variant exon3_exon4del p.(Gly4_Asn109del), a novel variant c.1159C&gt;T p.(Gln387*), and a previously presented but rare pathogenic variant c.1309C&gt;T p.(Arg437*) (NM_001396.5) in three families, respectively. In light of the updated American College of Medical Genetic and Genomics (ACMG) criterion, the variant of exon3_exon4del and c.1159C&gt;T were both classified as likely pathogenic (PSV1+PM6), while c1309C&gt;T was identified as pathogenic (PVS1+PS2_Moderate+PM2). Considering clinical features and molecular testimony, the three probands were confirmed diagnosed with MRD7. These three discovered variants were considered as the three causal mutations for MRD7. Prenatal diagnosis detected the heterozygous dominant variant of c.1159C&gt;T p.(Gln387*) in one of the fetuses, indicating a significant probability of MRD7, subsequently the gestation was intervened by the parents’ determination and professional obstetrical operation. On the other side, prenatal molecular genetic testing revealed wild-type alleles in the other two fetuses, and their parents both decided to sustain the gestation.Conclusion: We identified two novel and one rare mutation in DYRK1A which has broadened the spectrum of DYRK1A and provided evidence for the diagnosis of MRD7 at the molecular level. Besides, this study has supported the three families with MRD7 to determine the causative genetic factors efficiently and provide concise genetic counseling for the three families by using Trio-WES technology

Analysis of chromosomal structural variations in patients with recurrent spontaneous abortion using optical genome mapping

Background and aims: Certain chromosomal structural variations (SVs) in biological parents can lead to recurrent spontaneous abortions (RSAs). Unequal crossing over during meiosis can result in the unbalanced rearrangement of gamete chromosomes such as duplication or deletion. Unfortunately, routine techniques such as karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) cannot detect all types of SVs. In this study, we show that optical genome mapping (OGM) quickly and accurately detects SVs for RSA patients with a high resolution and provides more information about the breakpoint regions at gene level.Methods: Seven couples who had suffered RSA with unbalanced chromosomal rearrangements of aborted embryos were recruited, and ultra-high molecular weight (UHMW) DNA was isolated from their peripheral blood. The consensus genome map was created by de novo assembly on the Bionano Solve data analysis software. SVs and breakpoints were identified via alignments of the reference genome GRCh38/hg38. The exact breakpoint sequences were verified using either Oxford Nanopore sequencing or Sanger sequencing.Results: Various SVs in the recruited couples were successfully detected by OGM. Also, additional complex chromosomal rearrangement (CCRs) and four cryptic balanced reciprocal translocations (BRTs) were revealed, further refining the underlying genetic causes of RSA. Two of the disrupted genes identified in this study, FOXK2 [46,XY,t(7; 17)(q31.3; q25)] and PLXDC2 [46,XX,t(10; 16)(p12.31; q23.1)], had been previously shown to be associated with male fertility and embryo transit.Conclusion: OGM accurately detects chromosomal SVs, especially cryptic BRTs and CCRs. It is a useful complement to routine human genetic diagnostics, such as karyotyping, and detects cryptic BRTs and CCRs more accurately than routine genetic diagnostics