Benign recurrent intrahepatic cholestasis is an autosomal recessive disorder presenting with intermittent episodes of cholestatic jaundice. The initial episode of benign recurrent intrahepatic cholestasis tends to occur within the first two decades of a patient\'s life. Episodes can occur unprompted but can often be precipitated by infections or pregnancy. We report an interesting case of a 13-year-old girl presented with recurrent intrahepatic cholestasis. The patient has a unique homozygous USP53 genetic mutation, the first patient to present with this mutation within the South Asian region. The patient was initially misdiagnosed as a case of autoimmune hepatitis, and when presenting to our set-up was diagnosed as a case of benign recurrent intrahepatic cholestasis. The patient has since been managed on medication and remains regular in follow-up, responding well to treatment.

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder associated with progressive extrapyramidal signs, mental retardation, alopecia, and a variety of endocrine deficiencies, including diabetes mellitus, hypogonadism, and hypothyroidism. To date, approximately 98 genetically confirmed WSS families have been reported worldwide. This report focuses on a new genetic variant detected in 2 WSS-affected sisters with distinctive phenotypical features. The case under review is of special interest due to the multiple manifestations of WSS. This is the first family case of WSS identified in the Russian Federation. Although there is no specific treatment for WSS, genetic testing makes it possible to diagnose WSS, make a prognosis, and provide comprehensive patient-oriented treatment.

BACKGROUND: This study aims to analyze the pathogenic gene in a Chinese family with non-syndromic hearing loss and identify a novel mutation site in the TNC gene.
METHODS: A five-generation Chinese family from Anhui Province, presenting with autosomal dominant non-syndromic hearing loss, was recruited for this study. By analyzing the family history, conducting clinical examinations, and performing genetic analysis, we have thoroughly investigated potential pathogenic factors in this family. The peripheral blood samples were obtained from 20 family members, and the pathogenic genes were identified through whole exome sequencing. Subsequently, the mutation of gene locus was confirmed using Sanger sequencing. The conservation of TNC mutation sites was assessed using Clustal Omega software. We utilized functional prediction software including dbscSNV_AdaBoost, dbscSNV_RandomForest, NNSplice, NetGene2, and Mutation Taster to accurately predict the pathogenicity of these mutations. Furthermore, exon deletions were validated through RT-PCR analysis.
RESULTS: The family exhibited autosomal dominant, progressive, post-lingual, non-syndromic hearing loss. A novel synonymous variant (c.5247A > T, p.Gly1749Gly) in TNC was identified in affected members. This variant is situated at the exon-intron junction boundary towards the end of exon 18. Notably, glycine residue at position 1749 is highly conserved across various species. Bioinformatics analysis indicates that this synonymous mutation leads to the disruption of the 5\' end donor splicing site in the 18th intron of the TNC gene. Meanwhile, verification experiments have demonstrated that this synonymous mutation disrupts the splicing process of exon 18, leading to complete exon 18 skipping and direct splicing between exons 17 and 19.
CONCLUSIONS: This novel splice-altering variant (c.5247A > T, p.Gly1749Gly) in exon 18 of the TNC gene disrupts normal gene splicing and causes hearing loss among HBD families.

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene.
METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing.
RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein.
CONCLUSIONS: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

UNASSIGNED: Hydroxysteroid 17-beta dehydrogenase type 10 (HSD10) protein is a mitochondrial enzyme. Multisystemic involvement occurs in HSD10 deficiency as in other mitochondrial diseases. HSD10 deficiency (disease) is rare. Less than 40 index cases have been reported so far. A female patient is even rarer because of X-linked transmission. Five index female cases have been reported.
UNASSIGNED: We report a three-year-old female patient who was investigated due to microcephaly and global developmental delay. She had significant dysmorphic findings. The tiglylglycine peak was detected in urinary organic acid analysis. Other metabolic investigations and laboratory tests were unremarkable. Mild cerebral atrophy, mild ventricular dilation, thin corpus callosum, and an increase in T2 signal in the globus pallidus were revealed at brain magnetic resonance imaging. Heterozygous novel mutation in the HSD17B10 gene was found by whole-exome sequencing (WES) analysis. We started isoleucine-restricted diet and a \"cocktail\" of the mitochondrial vitamin.
UNASSIGNED: We will see HSD10 disease patients more frequently with the increasing use of WES and genetic panels. Thus, different findings and phenotypes of the HSD10 disease will be revealed.

UNASSIGNED: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders involving peripheral nervous system. Charcot-Marie-Tooth disease 4B1 (CMT4B1) is a rare subtype of CMT. CMT4B1 is an axonal demyelinating polyneuropathy with an autosomal recessive mode of inheritance. Patients with CMT4B1 usually manifested with dysfunction of the motor and sensory systems which leads to gradual and progressive muscular weakness and atrophy, starting from the peroneal muscles and finally affecting the distal muscles. Germline mutations in MTMR2 gene causes CMT4B1.
UNASSIGNED: In this study, we investigated a 4-year-old Chinese boy with gradual and progressive weakness and atrophy of both proximal and distal muscles. The proband\'s parents did not show any abnormalities. Whole-exome sequencing and Sanger sequencing were performed.
UNASSIGNED: Whole-exome sequencing identified a novel homozygous nonsense mutation (c.118A>T; p.Lys40*) in exon 2 of MTMR2 gene in the proband. This novel mutation leads to the formation of a truncated MTMR2 protein of 39 amino acids instead of the wild- type MTMR2 protein of 643 amino acids. This mutation is predicted to cause the complete loss of the PH-GRAM domain, phosphatase domain, coiled-coil domain, and PDZ-binding motif of the MTMR2 protein. Sanger sequencing revealed that the proband\'s parents carried the mutation in a heterozygous state. This mutation was absent in 100 healthy control individuals.
UNASSIGNED: This study reports the first mutation in MTMR2 associated with CMT4B1 in a Chinese population. Our study also showed the importance of whole-exome sequencing in identifying candidate genes and disease-causing variants in patients with CMT4B1.

Introduction: Primary ciliary dyskinesia (PCD) is a rare heterogeneous disease caused by abnormalities in motile cilia. In this case report, we first analyzed the clinical and genetic data of a proband who was suspected of having PCD on the basis of her clinical and radiological findings. Methods: Whole-exome sequencing was performed, and a variant in the RSPH4A gene was identified in the proband. Sanger sequencing was used for validation of RSPH4A variants in the proband, her sister, her daughter and her parents. Finally, the phenotypic features of the patient were analyzed, and the current literature was reviewed to better understand the gene variants in PCD related to hearing loss and the clinical manifestations of the RSPH4A variant in PCD. Results: The chief clinical symptoms of this proband included gradual mixed hearing loss, otitis media, anosmia, sinusitis, recurrent cough and infertility. Her DNA sequencing revealed a novel homozygous T to C transition at position 1321 within exon 3 of RSPH4A according to genetic testing results. This variant had never been reported before. The homozygous variant resulted in an amino acid substitution of tryptophan by arginine at position 441 (p.Trp441Arg). The same variant was also found in the proband\'s sister, and a heterozygous pathogenic variant was identified among immediate family members, including the proband\'s daughter and parents. Discussion: A literature review showed that 16 pathogenic variants in RSPH4A have been reported. Hearing loss had only been observed in patients with the RSPH4A (c.921+3_6delAAGT) splice site mutation, and the specific type of hearing loss was not described.

The clinical presentation of CD21 deficiency in 2 siblings caused by a novel mutation in the CD21 gene is reported, and the frequency of this mutation in the Danish population is explored. Successful treatment with IgG replacement in both patients with CD21 deficiency is also reported.

We reported a novel variant in Kallmann syndrome. It not only determines the clinical importance of whole exome sequencing for identification of genetic pathogenic variants, but also enriches the ANOS1 genetic spectrum of CHH patients in Chinese population.

Pseudohypoaldosteronism type 1 (PHA1) is a rare inherited disorder of resistance to aldosterone and presents with hyponatremia, hyperkalemia, and metabolic acidosis. Cohen syndrome (CS) is another rare inherited disease. Concurrent presentation with pseudohypoaldosteronism makes it so extraordinary and implies more challenges for clinicians. We report a case of a female with Cohen syndrome (novel mutation) and systemic pseudohypoaldosteronism, as well as the challenges we have encountered in the management of this patient.