Long-Read Sequencing Expands the Genotypic Spectrum of Patients With Mucopolysaccharidosis Type II.

The substantial genetic heterogeneity associated with mucopolysaccharidosis type II (MPS II) poses major challenges to current genetic testing. A comprehensive analysis of MPS II (CAMPS II), integrating long-range PCR with long-read sequencing (LRS), was established to identify IDS variants in 92 patients with clinically suspected MPS II. Comparative analysis against conventional genetic testing including multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing revealed concordant results in 75% (69/92) of cases, with discordant results in 25% (23/92) of cases.

Long-read sequencing enables comprehensive molecular genetic diagnosis of Fabry disease.

Background: The clinical diagnosis of Fabry Disease (FD) can be challenging due to the clinical heterogeneity, especially in females. Patients with FD often experience a prolonged interval between the onset of symptoms and receiving a diagnosis. Genetic testing is the gold standard for precise diagnosis of FD, however conventional genetic testing could miss deep intronic variants and large deletions or duplications.

Approach to the Patient: Diagnosis and Treatment With Growth Hormone of Turner Syndrome and Its Variants.

Context: Turner syndrome (TS) is characterized by a partial or complete absence of the second X chromosome in female individuals. Here, patients with Xp deletion involving SHOX haploinsufficiency caused by unbalanced X-autosome translocations were discussed and considered as TS variants.

Objective: This work aimed to expand the current knowledge of TS and unbalanced X-autosome translocations and to suggest the definition, clinical characteristics, diagnosis workflow, and growth hormone (GH) treatment strategy of TS and its variants.

FDXR-associated disease in a Chinese cohort: Unraveling expanded ocular phenotypes and genetic spectrum.

FDXR: associated disease is characterized by optic atrophy, acoustic neuropathy, and developmental delays. This study evaluated the ocular phenotypes and genetic features of patients with biallelic FDXR variants. Five individuals from unrelated non-consanguineous Chinese families with biallelic FDXR variants were identified using whole exome sequencing, Sanger sequencing, and co-segregation validation.

A deletion variant Arg616 of androgen receptor in a Chinese family with complete androgen insensitivity syndrome.

Complete androgen insensitivity syndrome (CAIS, OMIM; 300068) is a disorder of sex development with X-linked recessive inheritance. Cases of CAIS usually present as female phenotype, with primary amenorrhea and/or inguinal hernia. Family aggregation is a rare scenario.

Systematic assessment of the contribution of structural variants to inherited retinal diseases.

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined were subjected to WGS.

Systematic assessment of the contribution of structural variants to inherited retinal diseases.

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined was subjected to WGS.

Phenotypic and genetic characteristics of 130 patients with mucopolysaccharidosis type II: A single-center retrospective study in China.

Mucopolysaccharidosis Type II (MPS II) is a rare, progressive and ultimately fatal X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene. This report conducted a retrospective analysis to investigate the clinical characteristics, genotypes and management strategies in a large cohort of Chinese patients with MPS II. In this study, we explored 130 Chinese patients with MPS II between September 2008 and April 2022.

Clinical characteristics and molecular etiology of partial 17α-hydroxylase deficiency diagnosed in 46,XX patients.

Introduction: Complete 17α-hydroxylase deficiency (17OHD) is relatively common, with typical juvenile female genitalia, severe hypertension, hypokalemia, and the absence of sexual development, but partial (or non-classical) 17OHD (p17OHD) is extremely rare. The p17OHD patients can present with a broad spectrum of symptoms in 46,XX karyotype including various degree of spontaneous breast development after puberty, recurrent ovarian cysts, oligomenorrhea and infertility depending on specific gene mutations and other influencing factors.

Methods: This paper is a retrospective analysis of p17OHD cases from 1997 to 2021 in a Chinese tertiary hospital.

Identification and characterization of two DMD pedigrees with large inversion mutations based on a long-read sequencing pipeline.

Pathogenic large inversions are rarely reported on DMD gene due to the lack of effective detection methods. Here we report two DMD pedigrees and proposed a reliable pipeline to define large inversions in DMD patients. In the first pedigree, conventional approaches including multiplex ligation-dependent probe amplification, and whole-exome sequencing by next generation sequencing were failed to detect any pathologic variant.

Genotype-Phenotype Correlation Analysis and Identification of a Novel Mutation in Four Unrelated Chinese Patients with 5α-Reductase Deficiency.

Objective: The 5α-reductase type 2 deficiency is mainly caused by mutations in the gene. Our study aims to investigate the gene mutations and their corresponding manifestations.

Methods: Four unrelated Chinese patients with 46, XY ambiguous genitalia were studied.

Leber congenital amaurosis as an initial manifestation in a Chinese patient with thiamine-responsive megaloblastic anemia syndrome.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder, inherited by the defective SLC19A2 gene that encodes a high-affinity thiamine transporter (THTR-1). TRMA is characterized by the occurrence of classical triad manifestations including megaloblastic anemia, diabetes mellitus, and sensorineural deafness. In addition to the systemic manifestations, ophthalmic features can be present and include retinitis pigmentosa, optic atrophy, cone-rod dystrophy, maculopathy, and Leber congenital amaurosis.

Clinical characterization and the improved molecular diagnosis of autosomal dominant cone-rod dystrophy in patients with SCA7.

Purpose: To evaluate the retinal phenotype and genetic features of Chinese patients with spinocerebellar ataxia type 7 (SCA7).

Methods: Detailed ophthalmic examinations, including electroretinograms, fundus photography, fundus autofluorescence and optical coherence tomography, were performed to analyse the retinal lesions of patients with SCA7. A molecular genetic analysis was completed to confirm the number of CAG repeats in gene on the patients and their family members.

A Comprehensive Analysis of 2013 Dystrophinopathies in China: A Report From National Rare Disease Center.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive neuromuscular disorders caused by mutations in . A high-quality database of DMD/BMD is essential not only for clinical practice but also for fundamental research. Here, we aimed to build the largest Chinese national dystrophinopathy database using the National Rare Diseases Registry System of China.

Exonic rearrangements in DMD in Chinese Han individuals affected with Duchenne and Becker muscular dystrophies.

Exonic deletions and duplications within DMD are the main pathogenic variants in Duchenne and Becker muscular dystrophies (DMD/BMD). However, few studies have profiled the flanking sequences of breakpoints and the potential mechanism underlying the breakpoints in different fragile regions of DMD. In this study, 896 Chinese male probands afflicted with DMD/BMD were selected from unrelated families and analyzed using multiplex ligation-dependent probe amplification of the DMD gene, in which we identified exon deletions in 784 subjects and duplications in 112 subjects.

Whole exome sequencing identified a novel truncation mutation in the NHS gene associated with Nance-Horan syndrome.

Background: Nance-Horan syndrome (NHS) is an X-linked inheritance disorder characterized by bilateral congenital cataracts, and facial and dental dysmorphism. This disorder is caused by mutations in the NHS gene. However, NHS may be difficult to detect in individuals with subtle facial dysmorphism and dental abnormalities in whom congenital cataracts are the primary clinical manifestations.

A heterozygous mutation in RPGR associated with X-linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX).

Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years.

Rep1 copy number variation is an important genetic cause of choroideremia in Chinese patients.

Choroidermia (CHM) is an X-linked chorioretinal disorder caused by mutations in the Rab Escort Protein 1 (Rep-1) gene. Its diagnosis depends on clinical findings and genetic confirmation; however, mutations in Rep-1 gene are not always detected by standard Sanger sequencing. We therefore conducted multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (QPCR) in cases of Chinese CHM families in which sequencing all the exons and flanking intronic regions of the CHM gene had not identified a mutation or exons could not be amplified.

Clinical and genetic characteristics of 17 Chinese patients with glycogen storage disease type IXa.

Glycogen storage disease (GSD) type IXa is caused by PHKA2 mutation, which accounts for about 75% of all the GSD type IX cases. Here we first summarized the clinical data and analyzed the PHKA2 gene of 17 Chinese male patients suspected of having GSD type IXa. Clinical symptoms of our patients included hepatomegaly, growth retardation, and liver dysfunction.

Mutation Analysis of 16 Mucolipidosis II and III Alpha/Beta Chinese Children Revealed Genotype-Phenotype Correlations.

Mucolipidosis II and III alpha/beta are autosomal recessive diseases caused by mutations in the GNPTAB gene which encodes the α and β subunits of the N-acetylglucosamine-1-phosphotransferase. Clinically, mucolipidosis II (MLII) is characterized by severe developmental delay, coarse facial features, skeletal deformities, and other systemic involvement. In contrast, MLIII alpha/beta is a much milder disorder, the symptoms of which include progressive joint stiffness, short stature, and scoliosis.

Copy number variation sequencing-based prenatal diagnosis using cell-free fetal DNA in amniotic fluid.

Objective: The study aimed to determine whether cell-free fetal DNA (cffDNA) present in amniotic fluid supernatant can be used as a surrogate for amniocyte-based diagnosis of fetal chromosomal abnormalities.

Method: Amniocentesis was performed on 28 high-risk pregnancies. Amniocytes and the cffDNA fraction were prepared from the amniotic fluid samples.

[The mutation analysis of PAH gene and prenatal diagnosis in classical phenylketonuria family].

Objective: To characterize the mutation spectrum of phenylalanine hydroxylase (PAH) gene and perform prenatal diagnosis for families with classical phenylketonuria.

Methods: By stratified sequencing, mutations were detected in the exons and flaking introns of PAH gene of 44 families with classical phenylketonuria. 47 fetuses were diagnosed by combined sequencing with linkage analysis of three common short tandem repeats (STR) (PAH-STR, PAH-26 and PAH-32) in the PAH gene.