This case report presents the clinical manifestation and diagnostic testing of a 12-year-old male diagnosed with systemic infantile hyalinosis (SIH) at the Maternity and Children Hospital in Madinah in 2012. The patient presented with typical SIH symptoms, including painful joint contractures, hyperpigmented knuckles, gingival hypertrophy, subcutaneous nodules, and recurrent infections. Whole exome sequencing (WES) analysis identified a homozygous mutation in the ANTXR2 gene, which is a deletion in exon 13 (c.1074delT; p.A359HfsX50), confirming the diagnosis. Notably, this patient\'s survival beyond the typical age expectancy of SIH, which is usually within the first few years of life, challenges the usual prognosis associated with this disease. This case emphasizes the importance of early diagnosis through clinical suspicion confirmed by genetic analysis and highlights the variability in disease presentation and prognosis.

BACKGROUND: Feeding difficulties frequently co-occur with multisystem disorders attributed to rare genetic diseases. In this study, we aimed to describe the genetic manifestations and phenotype spectrum in infants experiencing feeding difficulties.
METHODS: This case series included infants under 6 months old with feeding difficulties admitted to the neonatal department of Children\'s Hospital, Zhejiang University School of Medicine from October 2018 to May 2022. All infants underwent whole-exome sequencing (WES) during hospitalisation, and their clinical phenotypes and genetic results were analyzed.
RESULTS: Among 28 infants studied, nine were preterm and 19 were full-term. Median admission age was 13.5 days (IQR 6.5, 35), with a median hospital stay of 16 days (IQR 10.5, 30). Overall, 12 (42.9%) cases were complicated with multiple malformations. Abnormal muscle tone (53.6%) and neurological issues (42.9%) were notable prevalent in these infants. Cranial MR abnormalities were noted in 96.2% of cases. Based on the combined analysis of WES results and clinical phenotypes, a total of 22 (78.3%) patients displayed disease-related genetic variation identified through WES; among them, 15 (53.6%) patients received genetic diagnoses, while 7 (25%) patients were suspected diagnoses. Positive findings were more frequent in full-term (89.5%) than preterm infants (55.6%). Ultimately, 24 (85.7%) patients were discharged alive, with 75% requiring post-discharge tube feeding. Following discharge, five patients developed new symptoms linked to genetic variants, and two patients died.
CONCLUSIONS: Feeding difficulty may constitute a facet of the phenotypic spectrum of rare genetic diseases. Whole-exome sequencing can enhance molecular diagnosis accuracy for infants with feeding difficulties.

A rare and challenging case of a preterm neonate with clinical and radiological signs of respiratory distress syndrome (RDS) since the first hour of life but was refractory to its standard treatment regimes like surfactant therapy and ventilation. Postmortem lung biopsy led us to the diagnosis of congenital pulmonary alveolar proteinosis (PAP). It occurs due to the aggregation of abnormal surfactant proteins and lipids in the alveoli, which hampers gas diffusion across the alveoli. It presents as respiratory distress at birth, and its diagnosis is often missed due to its resemblance with RDS. Although the exact etiology remains elusive, mutations in genes encoding surfactant and granulocyte-macrophage colony-stimulating factor (GM-CSF) pathway components have been implicated in the pathogenesis of PAP. Treatment options are limited and only supportive. Among all these, whole-lung lavage is the most widely used management modality but with limited success in neonates.

BACKGROUND: The 22q11.2 Deletion Syndrome (22q11.2 DS) presents unique healthcare challenges for affected individuals, families, and healthcare systems. Despite its rarity, 22q11.2 DS is the most common microdeletion syndrome in humans, emphasizing the need to understand and address the distinctive healthcare requirements of those affected. This paper examines the multifaceted issue of health service access and caregivers\' quality of life in the context of 22q11.2 DS in Brazil, a condition with diverse signs and symptoms requiring multidisciplinary care. This study employs a comprehensive approach to evaluate health service accessibility and the quality of life of caregivers of individuals with 22q11.2 DS. It utilizes a structured Survey and the WHOQOL-bref questionnaire for data collection.
RESULTS: Individuals with 22q11.2 DS continue to receive incomplete clinical management after obtaining the diagnosis, even in the face of socioeconomic status that enabled an average age of diagnosis that precedes that found in sample groups that are more representative of the Brazilian population (mean of 3.2 years versus 10 years, respectively). In turn, caring for individuals with 22q11.2 DS who face difficulty accessing health services impacts the quality of life associated with the caregivers\' environment of residence.
CONCLUSIONS: Results obtained help bridge the research gap in understanding how caring for individuals with multisystem clinical conditions such as 22q11.2 DS and difficulties in accessing health are intertwined with aspects of quality of life in Brazil. This research paves the way for more inclusive healthcare policies and interventions to enhance the quality of life for families affected by this syndrome.

UNASSIGNED: A case report of a six-year and five-month-old female admitted with typical symptoms of Rubinstein-Taybi syndrome is presented. Clinical and rehabilitation settings where she acquired her reading, writing, and communication skills are described.
UNASSIGNED: Because of her cognitive disabilities, a multidisciplinary and long-term intervention (2014-2020) was necessary. Treatment included orthoptic, psychomotor, logopedic, occupational, and neuropsychological care. Her family and school were involved.
UNASSIGNED: Increased attention led to decreased dysfunctional behaviors. Test results are still below average, but there has been significant improvement. Better communication skills resulted from increased phonetic range, improved articulation, lexical-semantic structure, comprehension, and production of sentences. Digital technologies played a significant role in enhancing her communication skills, not just in social interactions but also in school activities. The patient is oriented in time and space with the help of agendas and calendars. She can express her needs and compose concise narratives. As a result of acquiring functional skills, she is better equipped to handle real-life situations, which has led to increased social and family activities.
UNASSIGNED: This case report highlights the importance of personalized rehabilitation programs. Obtaining an early genetic diagnosis is crucial for timely tailored rehabilitation, and any delays in this process can hinder progress.

Autophagy phenomenon in the cell maintains proteostasis balance by eliminating damaged organelles and protein aggregates. Imbalance in autophagic flux may cause accumulation of protein aggregates in various neurodegenerative disorders. Regulation of autophagy by either calcium or chaperone play a key role in the removal of protein aggregates from the cell. The neuromuscular rare genetic disorder, GNE Myopathy, is characterized by accumulation of rimmed vacuoles having protein aggregates of β-amyloid and tau that may result from altered autophagic flux. In the present study, the autophagic flux was deciphered in HEK cell-based model for GNE Myopathy harbouring GNE mutations of Indian origin. The refolding activity of HSP70 chaperone was found to be reduced in GNE mutant cells compared to wild type controls. The autophagic markers LC3II/I ratio was altered with increased number of autophagosome formation in GNE mutant cells compared to wild type cells. The cytosolic calcium levels were also increased in GNE mutant cells of Indian origin. Interestingly, treatment of GNE mutant cells with HSP70 activator, BGP-15, restored the expression and refolding activity of HSP70 along with autophagosome formation. Treatment with calcium chelator, BAPTA-AM restored the cytoplasmic calcium levels and autophagosome formation but not LC3II/I ratio significantly. Our study provides insights towards GNE mutation specific response for autophagy regulation and opens up a therapeutic advancement area in calcium signalling and HSP70 function for GNE related Myopathy.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

BACKGROUND: X-chromosome inactivation (XCI) is an epigenetic process that occurs during early development in mammalian females by randomly silencing one of two copies of the X chromosome in each cell. The preferential inactivation of either the maternal or paternal copy of the X chromosome in a majority of cells results in a skewed or non-random pattern of X inactivation and is observed in over 25% of adult females. Identifying skewed X inactivation is of clinical significance in patients with suspected rare genetic diseases due to the possibility of biased expression of disease-causing genes present on the active X chromosome. The current clinical test for the detection of skewed XCI relies on the methylation status of the methylation-sensitive restriction enzyme (Hpall) binding site present in proximity of short tandem polymorphic repeats on the androgen receptor (AR) gene. This approach using one locus results in uninformative or inconclusive data for 10-20% of tests. Further, recent studies have shown inconsistency between methylation of the AR locus and the state of inactivation of the X chromosome. Herein, we develop a method for estimating X inactivation status, using exome and transcriptome sequencing data derived from blood in 227 female samples. We built a reference model for evaluation of XCI in 135 females from the GTEx consortium. We tested and validated the model on 11 female individuals with different types of undiagnosed rare genetic disorders who were clinically tested for X-skew using the AR gene assay and compared results to our outlier-based analysis technique.
RESULTS: In comparison to the AR clinical test for identification of X inactivation, our method was concordant with the AR method in 9 samples, discordant in 1, and provided a measure of X inactivation in 1 sample with uninformative clinical results. We applied this method on an additional 81 females presenting to the clinic with phenotypes consistent with different hereditary disorders without a known genetic diagnosis.
CONCLUSIONS: This study presents the use of transcriptome and exome sequencing data to provide an accurate and complete estimation of X-inactivation and skew status in a cohort of female patients with different types of suspected rare genetic disease.

Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.
Here, we interrogate 6045 whole genomes from Qatar-a Middle Eastern population with high consanguinity and understudied mutational burden-enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.
We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1-3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region.
This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.

Rare genetic diseases, often referred to as orphan diseases due to their low prevalence and limited treatment options, have long posed significant challenges to our medical system. In recent years, Messenger RNA (mRNA) therapy has emerged as a highly promising treatment approach for various diseases caused by genetic mutations. Chemically modified mRNA is introduced into cells using carriers like lipid-based nanoparticles (LNPs), producing functional proteins that compensate for genetic deficiencies. Given the advantages of precise dosing, biocompatibility, transient expression, and minimal risk of genomic integration, mRNA therapies can safely and effectively correct genetic defects in rare diseases and improve symptoms. Currently, dozens of mRNA drugs targeting rare diseases are undergoing clinical trials. This comprehensive review summarizes the progress of mRNA therapy in treating rare genetic diseases. It introduces the development, molecular design, and delivery systems of mRNA therapy, highlighting their research progress in rare genetic diseases based on protein replacement and gene editing. The review also summarizes research progress in various rare disease models and clinical trials. Additionally, it discusses the challenges and future prospects of mRNA therapy. Researchers are encouraged to join this field and collaborate to advance the clinical translation of mRNA therapy, bringing hope to patients with rare genetic diseases.