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BACKGROUND: Leber congenital amaurosis (LCA) is a congenital onset severe form of inherited retinal dystrophy (IRD) and a common cause of pediatric blindness. Disease-causing variants in at least 14 genes are reported to predispose LCA phenotype. LCA is inherited as an autosomal recessive disease. It can be an isolated eye disorder or as part of a syndrome, such as Senior Loken or Joubert syndrome. Sequencing studies from consanguineous populations have proven useful for novel variants identification; thus, the present study aimed to explore the genetic heterogeneity of 15 consanguineous Pakistani families, each segregating a severe IRD phenotype using targeted next generation sequencing. METHODS: This study enrolled 15 consanguineous families, each with multiple affected cases of retinal dystrophy phenotype. DNA was extracted from blood samples. Targeted panel sequencing of 344 known genes for IRDs was performed, followed by Sanger sequencing for segregation analysis. RESULTS: Data analysis revealed a total of eight reported (c.316C>T and c.506G>A in RDH12; c.864dup and c.1012C>T in SPATA7, as well as c.1459T>C, c.1062_1068del, c.1495+1G>A, c.998G>A in the CRB1, LCA5, TULP1, and IFT140 genes, respectively) and four novel homozygous (c.720+1G>T in LCA5, c.196G>C in LRAT, c.620_625del in PRPH2, and c.3411_3414del in CRB1) variants segregating with disease phenotype in each respective family. Furthermore, a novel heterozygous variant of CRB1 gene, i.e., c.1935delC in compound heterozygous condition was found segregating with disease phenotype in one large family with multiple consanguinity loops. CONCLUSION: Comprehensive molecular diagnosis of 15 consanguineous Pakistani families led to the identification of a total of 5 novel variants contributing to genetic heterogeneity of LCA-associated genes and helped to provide genetic counseling to the affected families.

AbstractIntroduction: Mucolipidosis II alpha/beta (ML II) is an autosomal recessive disorder with craniofacial dysmorphism and bone deformities. The variants in GNPTAB are associated with ML II. Materials and Methods: A female pediatric patient presented with bone deformities, mental and motor developmental abnormalities and craniofacial dysmorphism. We performed clinical whole-exome sequencing (WES) and verified the variants via qPCR, gap-PCR and Sanger sequencing. Results: Clinical WES identified a point variant c.1090C > T (p.R364*) and a copy number variation (CNV) in GNPTAB. Compared with normal control, GNPTAB expression was reduced in blood of the proband. Using Gap-PCR and Sanger sequencing, we identified the break point of CNV (NC_000012.11:g.102136912_102142973del), and successfully performed prenatal diagnosis for the proband’s mother. Conclusion: To our knowledge, this is the first report of this novel CNV associated with ML II. Our findings expand the genotypes related to ML II and contribute to the gene diagnosis of ML II. [ABSTRACT FROM AUTHOR]

Baller–Gerold syndrome (BGS, OMIM: 218600), RAPADILINO syndrome (OMIM 266280), and Rothmund–Thomson syndrome (RTS, OMIM 266280), which are caused in some cases by RECQL4 pathogenic variants, show autosomal recessive inheritance. Some refer to them collectively as RECQL4 syndromes. Most cases have been reported during infancy and childhood periods. However, there have been no reports of phenotypes resulting in a lethal course in the perinatal period. We identified two fetuses with biallelic RECQL4 pathogenic variants during the perinatal period. The two fetuses with RECQL4 syndrome showed structural abnormalities, including severely hypoplastic forearms and lower legs. One fetus also had severe pulmonary hypoplasia. One case resulted in neonatal death because of respiratory failure, and the other was artificially terminated during pregnancy. The RECQL4 pathogenic variants were identified by exome sequencing followed by Sanger sequencing. The biallelic RECQL4 pathogenic variants can induce a lethal skeletal disorder. [ABSTRACT FROM AUTHOR]

Background: Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II) is an autosomal recessive rare genetic condition marked by characteristic clinical symptoms of prenatal and post-natal growth retardation, reduced height, and microcephaly caused by variations in PCNT gene located on chromosome 21q22. Case presentation: Four patients of Indian origin with growth deficiency and additional clinical features of MOPDII were recruited from a tertiary health care center and whole exome sequencing was performed on blood samples from these patients. Data were analyzed using standard bioinformatic algorithms and possible causal variants identified. Out of 4, 2 patients were identified to have splice site variants, one had nonsense variant, and one with single nucleotide deletion leading to frameshift in PCNT. All identified variants were in homozygous state. The variant PCNT:c.3465-1G > A has previously been reported in two unrelated patients in Israeli Druze population. The c.9273 + 1G > A variant has been documented in two independent studies, one from the United states and the other from the United Kingdom. Two mutations, a nonsense c.5299C > T and a frameshift single nucleotide deletion c.4180delG are currently mentioned in few databases only. Conclusion: All four patients had significant microcephaly and growth retardation and the new variants were found to be likely pathogenic by in silico analysis. Early detection of the syndrome is essential for early interventions, proper genetic counseling and prenatal diagnosis. [ABSTRACT FROM AUTHOR]

Fucosidosis is a rare lysosomal storage disease caused by α-L-fucosidase deficiency following a mutation in the FUCA1 gene. This enzyme is responsible for breaking down fucose-containing glycoproteins, glycolipids, and oligosaccharides within the lysosome. Mutations in FUCA1 result in either reduced enzyme activity or complete loss of function, leading to the accumulation of fucose-rich substrates in lysosomes. Lysosomes become engorged with undigested substrates, which leads to secondary storage defects affecting other metabolic pathways. The central nervous system is particularly vulnerable, with lysosomal dysfunction causing microglial activation, inflammation, and neuronal loss, leading to the neurodegenerative symptoms of fucosidosis. Neuroinflammation contributes to secondary damage, including neuronal apoptosis, axonal degeneration, and synaptic dysfunction, exacerbating the disease process. Chronic neuroinflammation impairs synaptic plasticity and neuronal survival, leading to progressive intellectual disability, learning difficulties, and loss of previously acquired skills. Inflammatory cytokines and lysosomal burden in motor neurons and associated pathways contribute to ataxia, spasticity, and hypotonia, which are common motor symptoms in fucosidosis. Elevated neuroinflammatory markers can increase neuronal excitability, leading to the frequent occurrence of epilepsy in affected individuals. So, fucosidosis is characterized by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or angiokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients usually die at an early age. Treatment of fucosidosis is a great challenge, and there is currently no definitive effective treatment. Hematopoietic cell transplantation studies are ongoing in the treatment of fucosidosis. However, early diagnosis of this disease and treatment can be effective. In addition, the body's immune system decreases due to chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is high with this treatment. In another treatment method, gene therapy, the use of retroviral vectors, is promising due to their easy integration, high cell efficiency, and safety. In another treatment approach, enzyme replacement therapy, preclinical studies are ongoing for fucosidosis, but the blood–brain barrier is a major obstacle in lysosomal storage diseases affecting the central nervous system. Early diagnosis is important in fucosidosis, a rare disease, due to the delay in the diagnosis of patients identified so far and the rapid progression of the disease. In addition, enzyme replacement therapy, which carries fewer risks, is promising. [ABSTRACT FROM AUTHOR]

A couple presented to the office with an apparently healthy infant for a thorough clinical assessment, as they had previously lost two male children to a neurodegenerative disorder. They also reported the death of a male cousin abroad with a comparable condition. We aimed to evaluate a novel coding pathogenic variant c.1097T>A, PLA2G6, within the affected family, previously identified in a deceased cousin, but its clinical significance remained undetermined. A 200 bp PCR product of target genome (including codon 366 of PLA2G6) was amplified followed by enzymatic digestion (MboI) and sequencing. Structural pathogenic variant analysis was performed using PyMOL 2.5.4. In RFLP analysis, the mutant-type allele produced a single band of 200 bp, and the wild-type allele manifested as two bands of 112 bp and 88 bp. The pathogenic variant was identified in nine family members, including two heterozygous couples with consanguineous marriages resulting in affected children. It was predicted to be deleterious by multiple bioinformatic tools. The substitution of nonpolar isoleucine with polar asparagine of iPLA2 (Ile366Asn) resulted in a eense pathogenic variant (ATC>AAC). A missense variant (p. Ile366Asn) in the PLA2G6 gene is associated with clinically evident infantile neuroaxonal dystrophy, which is transmitted in an autosomal recessive pattern, and is also predicted to be dysfunctional by bioinformatic analyses. [ABSTRACT FROM AUTHOR]

The purpose of this article was to report a rare case of mucopolysaccharidosis (MPS) type-I, Hurler–Scheie affecting a 10-year-old boy with a combination of ophthalmological, skeletal, neurological, orodental, and radiological findings. MPSs are a group of lysosomal storage disorders caused by inborn errors of glycosaminoglycan metabolism. MPS type-I is a rare autosomal recessive disorder that is clinically progressive caused by deficiency of the lysosomal enzyme, α-L-iduronidase, which is required to break down heparan and dermatan sulfates resulting in progressive accumulation of glycosaminoglycans within the lysosomes, subsequently leading to multiorgan dysfunction and damage. Newer treatment modalities such as hematopoietic stem cell transplantation and enzyme-replacement therapy have increased the life span of many MPS patients and created the need to improve the management of ocular symptoms.

Sjogren-Larsson syndrome (SLS) is an autosomal recessive ichthyotic syndrome characterized by a triad of congenital ichthyosis, mental retardation, and diplegia or tetraplegia. It occurs due to the defect in the gene responsible for encoding the enzyme fatty aldehyde dehydrogenase. Accumulating these abnormal aldehyde lipids in the skin and brain leads to clinical symptoms. This case report presents three siblings, born of a nonconsanguineous marriage, with a unique and rare manifestation of SLS. The siblings, aged 7, 5, and 3 years, respectively, exhibited pruritic dry, scaly rashes since infancy, along with abnormal gait and mental retardation. Genetic examination confirmed a homozygous mutation of the ALDH3A2 gene, leading to the diagnosis of SLS. Treatment involving capsule acitretin and a multidisciplinary approach resulted in a significant reduction in dryness and scaling. The case underscores the importance of early SLS diagnosis to mitigate morbidity and improve the quality of life for affected individuals.

Background: Autosomal recessive hypercholesterolemia (ARH), a genetic disorder of the affecting lipid metabolism. We present a child with this disorder wo was long undiagnosed, for many years. Clinical Description: An 8-year-old girl presented with multiple soft, painless, progressively increasing since the age of 2 years. Although lipid profiles had been found to be abnormal, she was not evaluated nor treated till 8 years of age. On examination, the swellings were present over upper and lower limbs and buttocks. Management and Outcome: Low-density lipoprotein (LDL) levels were elevated. Histopathology of the lesions confirmed xanthoma with immunohistochemistry being positive for CD 68 and ki67 index - 15%–20%. Next-generation sequencing homozygous mutation involving intron 15 of chromosome variant c2312-1G > A, causing loss of function variant in gene LDL receptor. The child was treated with gradually increasing doses of atorvastatin, with periodic echocardiography. There was progressive lowering of LDL over 6 months. Conclusion: Ignorance among pediatricians regarding this rare entity of ARH may result in lack of initiation of treatment for years, which may lead to detrimental cardiovascular complications in later life. Genetic analysis and prompt treatment can help in improving lipid parameters.

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder caused by loss of function mutations in the ADA2 gene (previously the CECR1 gene) on chromosome 22q11. The clinical spectrum of the disease is remarkably broad, and its presentations mimic features of polyarteritis nodosa, such as livedoid rash, hematological abnormalities (e.g., cytopenia), early‐onset stroke, hypogammaglobulinemia, and systemic inflammation. Early diagnosis and treatment of DADA2 are crucial, as the clinical features could be potentially life‐threatening but treatable. In this study, a 17‐year‐old male patient is reported with DADA2 whose symptoms mimic those of polyarteritis nodosa. A 17‐year‐old male patient presented with a 14‐year history of abdominal pain, hypertension, and cutaneous lesions initially attributed to polyarteritis nodosa (PAN). He was referred to our center due to ongoing abdominal pain. An abdominal and pelvic computed tomography scan with contrast revealed a retroperitoneal hemorrhage compressing the left kidney. Given his history of abdominal pain, hypertension, hemiparesis, transient ischemic attacks (TIA), anemia, cutaneous lesions, and retroperitoneal hemorrhage, DADA2 was suspected, and a genetic test confirmed the diagnosis. Treatment with anti‐TNF (Adalimumab) was initiated, resulting in noticeable improvement. In the follow up, fever, abdominal pain and TIA episodes were subsided and now he has a good clinical condition. Considering DADA2 and conducting a broad screening for other manifestations is recommended for patients presenting with PAN‐like symptoms. These patients may become symptomatic later in life, and early diagnosis allows for the consideration of disease‐specific treatment options. [ABSTRACT FROM AUTHOR]

Background/Objectives: Hearing loss (HL) is a significant global health concern, affecting approximately 1 in every 1000 newborns, with over half of these cases attributed to genetic factors. This study focuses on identifying the genetic basis of autosomal recessive non-syndromic hearing loss (ARNSHL) in a consanguineous Emirati family. Methods: Clinical exome sequencing (CES) was performed on affected members of the family, followed by Sanger sequencing to validate the findings. Specific primers were used for PCR amplification of target CDH23 exons. Mutations were analyzed using various computational tools to assess their pathogenicity. Results: We identified two heterozygous mutations in the CDH23 gene: a novel nonsense variant (c.264G>A, p.Trp88Ter) and a missense variant (c.5168G>A, p.Arg1723His). Both mutations were found in trans configuration, suggesting a compound heterozygous state contributing to the phenotype. In silico analysis predicted a significant impact on protein function, potentially leading to the observed ARNSHL. Conclusions: This study emphasizes the complexity of genetic factors in hearing loss, particularly in highly consanguineous populations. The identification of both nonsense and missense mutations in the CDH23 gene enhances understanding of its role in hearing loss and provides essential insights for genetic counseling and future therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: Hearing loss is a frequent sensory impairment type in humans, with about 50% of prelingual cases being attributed to genetic factors. Autosomal recessive hearing loss (ARHL) exhibits great locus heterogeneity and is responsible for 70%–80% of hereditary nonsyndromic cases. Methods: A total of 90 unrelated Brazilian individuals were selected for having hearing loss of presumably autosomal recessive inheritance, either born from consanguineous marriages or belonging to families with two or more affected individuals in the sibship and most cases were of normal hearing parents. In all cases, common pathogenic variants in GJB2 (c.35delG), GJB6 [del(GJB6-D13S1830) and del(GJB6-D13S1854)] and MT-RNR1 (m.1555A>G) were discarded and most were previously assessed by complete Sanger sequencing of GJB2. Their genetic material was analyzed through next-generation sequencing, targeting 99 hearing loss-related genes and/or whole exome sequencing. Results: In 32 of the 90 probands (36,7%) causative variants were identified, with autosomal recessive inheritance confirmed in all, except for two cases due to dominant variants (SIX1 and P2RX2). Thirty-nine different causative variants were found in 24 different known hearing loss-associated genes, among which 10 variants are novel, indicating wide genetic heterogeneity in the sample, after exclusion of common pathogenic variants. Despite the genetic heterogeneity, some genes showed greater contribution: GJB2 , CDH23 , MYO15A , OTOF , and USH2A. Conclusion: The present results confirmed that next-generation sequencing is an effective tool for identifying causative variants in autosomal recessive hearing loss. To our knowledge, this is the first report of next-generation sequencing being applied to a large cohort of pedigrees with presumable autosomal recessive hearing loss in Brazil and South America. [ABSTRACT FROM AUTHOR]

Introduction: Hearing loss is a frequent sensory impairment type in humans, with about 50% of prelingual cases being attributed to genetic factors. Autosomal recessive hearing loss (ARHL) exhibits great locus heterogeneity and is responsible for 70%-80% of hereditary nonsyndromic cases. Methods: A total of 90 unrelated Brazilian individuals were selected for having hearing loss of presumably autosomal recessive inheritance, either born from consanguineous marriages or belonging to families with two or more affected individuals in the sibship and most cases were of normal hearing parents. In all cases, common pathogenic variants in GJB2 (c.35delG), GJB6 [del(GJB6-D13S1830) and del(GJB6-D13S1854)] and MT-RNR1 (m.1555A>G) were discarded and most were previously assessed by complete Sanger sequencing of GJB2. Their genetic material was analyzed through next-generation sequencing, targeting 99 hearing loss-related genes and/or whole exome sequencing. Results: In 32 of the 90 probands (36,7%) causative variants were identified, with autosomal recessive inheritance confirmed in all, except for two cases due to dominant variants (SIX1 and P2RX2). Thirty-nine different causative variants were found in 24 different known hearing loss-associated genes, among which 10 variants are novel, indicating wide genetic heterogeneity in the sample, after exclusion of common pathogenic variants. Despite the genetic heterogeneity, some genes showed greater contribution: GJB2, CDH23, MYO15A, OTOF, and USH2A. Conclusion: The present results confirmed that next-generation sequencing is an effective tool for identifying causative variants in autosomal recessive hearing loss. To our knowledge, this is the first report of next-generation sequencing being applied to a large cohort of pedigrees with presumable autosomal recessive hearing loss in Brazil and South America. [ABSTRACT FROM AUTHOR]

Introduction: In the present study we describe atypical cases with bright and enlarged fetal kidneys identified on fetal ultrasound with different genetic etiologies. Methods: Exome sequencing was undertaken after prenatal counseling and after the initial diagnosis of enlarged fetal kidneys was made on ultrasound for four cases and the results were then correlated. Results: In the present study we identified underlying variants in ACE, ETFA, PKD1, and MKS1 gene where the atypical presentation of fetal kidneys was noted either as a part of spectrum of syndrome or alone. Conclusions: In the era of exome sequencing, targeted gene sequencing is getting replaced and for better. However not all answers are direct, and sometimes the variant categorization is dependent on the acumen and agreement of all those involved in the process. It includes those involved the diagnostic as well those catering to the patients. It is very important to be updated on the relevance of multiple gene in causing similar phenotypes particularly in the prenatal context were coming up with a timely diagnosis is very important for any sort of intervention. [ABSTRACT FROM AUTHOR]

This article discusses the natural history of dystonia in patients with SYNE1 ataxia, a late-onset autosomal recessive cerebellar syndrome. The study focuses on a Brazilian cohort of seven patients who were evaluated over a five-year period. The researchers found that dystonia in SYNE1 ataxia is rare but can manifest as focal hand dystonia or upper extremity dystonia. The article provides detailed clinical and demographic features of the patients and discusses the progression of dystonia symptoms over time. Additionally, the article explores the relationship between the use of trihexyphenidyl and muscle activity in patients with ATX-SYNE1, a form of autosomal recessive cerebellar ataxia. It presents neuroimaging results, neurophysiological findings, blood work, and genetic tests related to the condition. The article suggests that cerebellar abnormalities may contribute to the development of dystonic symptoms in ATX-SYNE1 patients and concludes that dystonia should be considered as part of the multisystemic phenotype of ATX-SYNE1. [Extracted from the article]

A cell’s ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3’ end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease. [ABSTRACT FROM AUTHOR]

Sjogren-Larsson syndrome (SLS) is an autosomal recessive ichthyotic syndrome characterized by a triad of congenital ichthyosis, mental retardation, and diplegia or tetraplegia. It occurs due to the defect in the gene responsible for encoding the enzyme fatty aldehyde dehydrogenase. Accumulating these abnormal aldehyde lipids in the skin and brain leads to clinical symptoms. This case report presents three siblings, born of a nonconsanguineous marriage, with a unique and rare manifestation of SLS. The siblings, aged 7, 5, and 3 years, respectively, exhibited pruritic dry, scaly rashes since infancy, along with abnormal gait and mental retardation. Genetic examination confirmed a homozygous mutation of the ALDH3A2 gene, leading to the diagnosis of SLS. Treatment involving capsule acitretin and a multidisciplinary approach resulted in a significant reduction in dryness and scaling. The case underscores the importance of early SLS diagnosis to mitigate morbidity and improve the quality of life for affected individuals. [ABSTRACT FROM AUTHOR]

BackgroundPrimary coenzyme Q10 (CoQ10) deficiency is an autosomal recessive genetic disease caused by mitochondrial dysfunction. Variants in Coenzyme Q8B (COQ8B) can cause primary CoQ10 deficiency. COQ8B-related glomerulopathy is a recently recognized glomerular disease that most often presents as steroid-resistant nephrotic syndrome (SRNS) in childhood. The disease often progresses to kidney failure and the renal histopathology is most commonly focal segmental glomerulosclerosis (FSGS).MethodsFour SRNS cases (2 females and 2 males) from 2 unrelated families who were followed clinically for nearly 3 years. Clinical exome testing and analyses were performed by MyGenostics Laboratory in China to evaluate unexplained proteinuria given the strong family history of glomerular disease and histologic evidence of SRNS. Pathogenic variants were identified in COQ8B in the exome studies and confirmed by direct sequencing.ResultsClinical exome sequencing revealed biallelic variants of the COQ8B gene in 2 families. In the Family 1, the oldest of three affected siblings died of renal failure at 11 years of age. Based on the results of genetic testing which identified a homozygous variant of COQ8B, the other two affected siblings with mild proteinuria and normal renal function were treated with CoQ10 oral supplementation at an early stage. Coenzyme Q10 treatment was effective in reducing proteinuria levels in both patients from Family 1 over the first 6 months and the two patients still have low-level proteinuria and normal renal function at nearly three years. In Family 2, clinical exome sequencing revealed a compoundheterozygous variants of COQ8B in a patient with biopsy- proven FSGS. His disease was unresponsive to prior treatment with glucocorticoids and cyclosporine. Oral CoQ10 was initiated based on his genetic diagnosis and was it was effective in reducing proteinuria over the first 5 months months of therapy. However after 1 year, his disease progressed tokidney failure. Kidney transplantation was performed at 5 years of age and his condition has been stable without rejection and no recurrence of disease.ConclusionsCOQ8B gene variant-related glomerulopathy often presents as SRNS without obvious extrarenal manifestations. The histopathology is mainly FSGS and follows an autosomal recessive mode of inheritance. Some patients may benefit from early coenzyme Q10 supplementation. For patients whose disease progresses to kidney failure, kidney transplantation can be an effective treatment. For children with unexplained proteinuria and abnormal renal function, genetic testing should be performed early in the course of disease to guide therapy where possible and improve prognosis.

Osteopetrosis is a bone condition caused by an abnormality in the function of osteoclasts. The absence of normal osteoclasts results in aberrant primary skeleton development and subsequent pathological bone turnover. When a blind patient presented to the hospital with recurrent pus discharge and was diagnosed with osteopetrosis, a unique radiological finding emerged.

Objective To report a case of autosomal recessive hypotrichosis type 7, and to discuss the mutations of LIPH gene in this family. Methods The clinical data of the case were collected. The genomic DNA was extracted from the peripheral blood of the patient and her parents. The high-throughput sequencing method was used to detect the sequence mutations of each exon in the coding region of all genes, and the gene mutation sites were determined. The mutant genes were verified by PCR-Sanger sequencing and bioinformatics analysis. Results The patient had a compound heterozygous mutations of LIPH gene c.409C>T (p.Gln137*) in exon 2 and c.742C>A (p.His248Asn) in exon 6, which were from the patient's father and mother, respectively. c.409C>T (p.Gln137*) had not been reported before. The results of bioinformatics analysis showed that the 137th Gln sequence and 248th His sequence of LIPH protein were highly conserved in multiple species. The structures of the corresponding proteins were altered after the mutation of the two sites compared to wild-type proteins, and the two mutations were suspected to be pathogenic mutations according to ACMG guidelines. Conclusion The compound heterozygous mutations of LIPH gene c.409C>T (p.Gln137*) in exon 2 and c.742C>A (p.His248Asn) in exon 6 are the cause of autosomal recessive hypotrichosis type 7 in this case.

AimsWerner Syndrome is a rare premature ageing autosomal recessive disorder caused by pathogenic variants in the WRN gene. People with Werner Syndrome may develop diabetes mellitus. Chronic foot ulceration is seen, with some characteristics overlapping with diabetic foot disease. However, the clinical course of the ulceration is atypical of diabetic foot disease. We present four siblings from an Irish Traveller family with Werner Syndrome to highlight the complexity of this condition. The Irish Traveller population are an indigenous, endogamous population in which consanguinity is common. As a result, rare autosomal recessive disorders are prevalent among this population:. Methods: We describe our experience managing the complex foot disease seen in all four siblings. Foot complications present in the siblings include painful peripheral neuropathy, chronic foor ulceration, underlying osteomyelitis and acral melanoma. Results: The cases are described individually, with a particular focus on the complex foot disease associated with the condition. Conclusions: Although the siblings attend a diabetic foot clinic, we suggest that the combination of clinical features seen in these cases is unique to Werner syndrome and warrants the title 'Werner Syndrome' (rather than 'Diabetic') foot. [ABSTRACT FROM AUTHOR]

CAD (MIM*114010) encodes a large multifunctional protein with the enzymatic activity of the first three enzymes initiating and controlling the de novo pyrimidine biosynthesis pathway. Biallelic pathogenic variants in CAD cause the autosomal recessive developmental and epileptic encephalopathy 50 (MIM #616457) or CAD deficiency presenting with epilepsy, status epilepticus (SE), neurological deterioration and anemia with anisopoikilocytosis. Mortality is around 9% of patients, mainly related to the no use of its specific treatment with uridine. Majority of reported cases have an early onset during infancy, with some few starting later in childhood. Here we report a deceased female patient with CAD deficiency whose epilepsy started at 14 years. She showed a rapid neurologic deterioration including cognitive decline, electroencephalographic background slowing which later evolved to a fatal refractory SE and supra and infratentorial atrophy on neuroimaging. Anemia developed after SE onset. her post-mortem whole exome sequencing identified biallelic missense variants in CAD (NM_004341.5): c.[2944G > A];[5366G > A] p.[(Asp982Asn)];[(Arg1789Gln)]. Our review of twenty-eight reported cases (2015–2023) revealed an epilepsy age onset from neonatal period to 7 years and the SE prevalence of 46 %. With our case, we highlight the relevance of suspecting this treatable condition in older patients and in SE with no evident etiology. [ABSTRACT FROM AUTHOR]

Agammaglobulinemia is a rare inherited immunodeficiency disorder characterized by low or absent B cells with absent immunoglobulins. While X-linked agammaglobulinemia (XLA) is the most common type other genetic forms of agammaglobulinemia have been identified. During early childhood, passively transferred maternal Immunoglobulin G protects against various infections. The depletion of these antibodies begins between 6 and 12 months of age, resulting in recurrent sinusitis, bronchitis, and pneumonia in children with X-linked agammaglobulinemia. However, less common autosomal recessive forms of agammaglobulinemia present with more severe clinical features, leading to earlier diagnosis. Herein we present the case of a two-month-old male with IGLL1 gene defect and different clinical findings of family members with the same mutation. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) poses a significant threat to eye health worldwide, with prevalence rates of 1 in 5000 worldwide. This genetically diverse retinopathy is characterized by the loss of photoreceptor cells and atrophy of the retinal pigment epithelium. Despite the involvement of more than 3000 mutations across approximately 90 genes in its onset, finding an effective treatment has been challenging for a considerable time. However, advancements in scientific research, especially in gene therapy, are significantly expanding treatment options for this most prevalent inherited eye disease, with the discovery of new compounds, gene-editing techniques, and gene loci offering hope for more effective treatments. Gene therapy, a promising technology, utilizes viral or non-viral vectors to correct genetic defects by either replacing or silencing disease-causing genes, potentially leading to complete recovery. In this review, we primarily focus on the latest applications of gene editing research in RP. We delve into the most prevalent genes associated with RP and discuss advancements in genome-editing strategies currently employed to correct various disease-causing mutations. [ABSTRACT FROM AUTHOR]

This study aimed to identify whether gyrate atrophy of the choroid and retina (GACR) heterozygous individuals have possible clinical manifestations and to explore the potential pathogenic mechanism. In this retrospective study, we surveyed a two-generation pedigree of an individual diagnosed with GACR. Two family members underwent ophthalmological, hematologic, and genetic tests. An arginine-restricted diet with vitamin B6 supplementation was implemented; clinical assessments were repeated every 3 months during follow-up. The relative OAT mRNA expression was determined using a real-time quantitative polymerase chain reaction. The 19-year-old compound heterozygous daughter (OAT: c.1186C>T; c.748C>T) had bilateral pathologic myopia, posterior staphyloma, chorioretinal atrophy, macular abnormalities, and elevated hematologic ornithine. The 54-year-old heterozygous mother (OAT: c.1186C>T) presented with bilateral pathologic myopia, asymmetric posterior staphyloma, retina and choroidal capillary layer atrophy, retinal pigment epithelium abnormalities, and mildly elevated hematologic ornithine. Compared to normal individuals, the daughter and mother had 29% and 46% relative OAT mRNA expression, respectively (p < 0.001). We believe that this is the first report of a carrier of one OAT variant allele exhibiting a mild phenotype, suggesting that family members should be aware of the possibility of clinical involvement in carriers with some autosomal recessive conditions. Additional data suggest that nonsense-mediated, decay-initiated mRNA degradation may cause GACR. [ABSTRACT FROM AUTHOR]

Monoallelic pathogenic HMBS variants are a well‐established cause of acute intermittent porphyria (AIP), whereas biallelic pathogenic variants may cause HMBS‐related leukoencephalopathy which remains a poorly characterized disorder. We describe an 8‐year‐old girl with hypotonia, hearing impairment, horizontal nystagmus, bilateral strabismus, impaired visual acuity, and optic nerve atrophy. She had no epilepsy but sleep electroencephalogram showed paroxysmal changes in the right hemisphere with secondary generalizations. Brain magnetic resonance imaging was unremarkable apart from a few small white matter hyperintensities. Exome sequencing (ES) initially prioritized a SCN3A c.3822G>A de novo variant whose sole causative role was eventually questioned as not fully compatible with symptoms. ES reanalysis revealed a homozygous c.674G>A HMBS variant. In the monoallelic form this variant is a known cause of AIP, whereas in trans with another HMBS pathogenic variant it was associated with the HMBS‐related leukoencephalopathy in four individuals. Despite lack of signs/symptoms of porphyria, literature analysis suggested that HMBS c.674G>A likely contributed to the disease either as the sole cause or together with SCN3A c.3822G>A as a part of blended phenotype. Our report adds to the relatively small number of described cases of HMBS‐related leukoencephalopathy and emphasizes that autosomal recessive form of HMBS disease can be present in the absence of porphyria symptoms. [ABSTRACT FROM AUTHOR]

Pathogenic variants of the SOHLH1 gene are responsible for an autosomal recessive form of ovarian dysgenesis; this gene encodes a transcription factor expressed early in spermatogonia and oocytes and contributes to folliculogenesis. Previously, four affected women from two unrelated families reported homozygous variants in the SOHLH1 gene, but none had a history of gonadal malignancy or a histologic description. We present two sisters and their paternal great-aunt with a history of primary amenorrhea, pubertal delay, and hypergonadotrophism who came from an inbred Mexican family. The proband was the younger sister who was referred for bilateral dysgerminoma. She had a normal blood karyotype, and whole-exome sequencing analysis revealed a novel homozygous missense variant, c.275C>T, in SOHLH1; several family members were also analyzed. In addition to pure dysgerminoma, histopathological analysis revealed an ovarian cortex with fibrosis and almost total absence of follicles. This work confirms the inheritance of ovarian dysgenesis 5, supports the occurrence of cell loss in mouse models, and suggests that affected women should undergo periodic imaging surveillance due to the likely risk of tumor development. [ABSTRACT FROM AUTHOR]

Primary microcephaly is characterized by a head circumference prenatally or at birth that falls below three standard deviations from age‐, ethnic‐, and sex‐specific norms. Genetic defects are one of the underlying causes of primary microcephaly. Since 2014, five variants of the SASS6 gene have been identified as the cause of MCPH 14 in three reported families. In this study, we present the genetic findings of members of a nonconsanguineous Chinese couple with a history of microcephaly and fetal growth restriction (FGR) during their first pregnancy. Utilizing trio whole‐exome sequencing, we identified compound heterozygous variants involving a frameshift NM_194292.3:c.450_453del p.(Lys150AsnfsTer7) variant and a splice region NM_194292.3:c.1674+3A>G variant within the SASS6 gene in the affected fetus. Moreover, reverse transcriptase‐polymerase chain reaction from RNA of the mother's peripheral blood leukocytes revealed that the c.1674+3A>G variant led to the skipping of exon 14 and an inframe deletion. To the best of our knowledge, the association between FGR and SASS6‐related microcephaly has not been reported, and our findings confirm the pivotal role of SASS6 in microcephaly pathogenesis and reveal an expanded view of the phenotype and mutation spectrum associated with this gene. [ABSTRACT FROM AUTHOR]

Usher syndrome (USH) is an autosomal recessive genetic disorder and a leading cause of simultaneous hearing and vision loss. The aim of this paper is to provide a detailed review of Usher syndrome, including its pathogenesis, clinical symptoms, diagnostic methods, the role of sport in the lives of athletes and sportspeople with Usher syndrome and available therapeutic options. Understanding this disease is crucial for early detection and the implementation of appropriate therapeutic interventions. Currently, Usher syndrome is classified into three main types (I, II, and III), differentiated by the degree and progression of hearing and vision loss. Type I is characterized by profound congenital deafness and early-onset retinitis pigmentosa. Type II presents with moderate to severe hearing loss and later onset of visual problems. Type III is the rarest, with progressive hearing and vision loss that occurs later in life. The genetic basis of Usher syndrome is linked to mutations in various genes that affect proteins essential for the proper functioning of the inner ear and retina. Early diagnosis and an interdisciplinary approach to treatment are key to improving the quality of life for those affected by this disease. Ongoing research into the genetic mechanisms and potential therapies offers hope for future successful treatments.

IntroductionHearing loss is a frequent sensory impairment type in humans, with about 50% of prelingual cases being attributed to genetic factors. Autosomal recessive hearing loss (ARHL) exhibits great locus heterogeneity and is responsible for 70%–80% of hereditary nonsyndromic cases.MethodsA total of 90 unrelated Brazilian individuals were selected for having hearing loss of presumably autosomal recessive inheritance, either born from consanguineous marriages or belonging to families with two or more affected individuals in the sibship and most cases were of normal hearing parents. In all cases, common pathogenic variants in GJB2 (c.35delG), GJB6 [del(GJB6-D13S1830) and del(GJB6-D13S1854)] and MT-RNR1 (m.1555A>G) were discarded and most were previously assessed by complete Sanger sequencing of GJB2. Their genetic material was analyzed through next-generation sequencing, targeting 99 hearing loss-related genes and/or whole exome sequencing.ResultsIn 32 of the 90 probands (36,7%) causative variants were identified, with autosomal recessive inheritance confirmed in all, except for two cases due to dominant variants (SIX1 and P2RX2). Thirty-nine different causative variants were found in 24 different known hearing loss-associated genes, among which 10 variants are novel, indicating wide genetic heterogeneity in the sample, after exclusion of common pathogenic variants. Despite the genetic heterogeneity, some genes showed greater contribution: GJB2, CDH23, MYO15A, OTOF, and USH2A.ConclusionThe present results confirmed that next-generation sequencing is an effective tool for identifying causative variants in autosomal recessive hearing loss. To our knowledge, this is the first report of next-generation sequencing being applied to a large cohort of pedigrees with presumable autosomal recessive hearing loss in Brazil and South America.

Primary hyperoxaluria (PH) type 1 is a rare autosomal recessive disorder of glyoxylate metabolism. Its prevalence is 1–3 cases/million people. Glyoxylate is the precursor of oxalate which is believed to be produced by oxidation in liver peroxisomes. Serine-pyruvate aminotransferase/alanine-glyoxylate aminotransferase is an enzyme involved in the metabolism of glyoxylate. In the absence of this enzyme, oxalate and glycolate are overproduced leading to hyperoxaluria. This causes urolithiasis or nephrocalcinosis, which are conditions caused by the deposition of calcium oxalate. Due to its rarity and heterogeneous phenotype, it remains unrecognized due to which diagnosis is delayed, ending up in end-stage renal disease (ESRD) and ultimately death. Hence, early diagnosis and simultaneous hepatorenal transplant remain the mainstay to avoid systemic oxalosis. Here, we discuss a case of a 43-year-old female who underwent combined liver–kidney transplant with a history of multiple episodes of renal calculi since childhood ultimately landing into ESRD in view of PH type 1.

BackgroundInherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone-rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype-phenotype correlations.ResultsGenetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone-rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype-phenotype correlation in these patients.ConclusionsThe authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone-rod and cone dystrophies.

Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in 2 independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to WT BMMs. Osteoclast formation induced by RANKL was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders. [ABSTRACT FROM AUTHOR]

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD. [ABSTRACT FROM AUTHOR]

Background: MUTYH germline monoallelic variants have been detected in a number of patients affected by breast/ovarian cancer or endometrial cancer, suggesting a potential susceptibility role, though their significance remains elusive since the disease mechanism is normally recessive. Hence, the aim of this research was to explore the hypothesis that a second hit could have arisen in the other allele in the tumor tissue. Methods: we used Sanger sequencing and immunohistochemistry to search for a second MUTYH variant in the tumoral DNA and to assess protein expression, respectively. Results: we detected one variant of unknown significance, one variant with conflicting interpretation of pathogenicity and three benign/likely benign variants; the MUTYH protein was not detected in the tumor tissue of half of the patients, and in others, its expression was reduced. Conclusions: our results fail to demonstrate that germinal monoallelic MUTYH variants increase cancer risk through a LOH (loss of heterozygosity) mechanism in the somatic tissue; however, the absence or partial loss of the MUTYH protein in many tumors suggests its dysregulation regardless of MUTYH genetic status. [ABSTRACT FROM AUTHOR]

Respiratory distress in the newborn is associated with numerous etiologies, some common and some rare. When respiratory distress is accompanied by laterality defects, namely, situs inversus (SI), the index of suspicion for comorbid primary ciliary dyskinesia (PCD) should be raised. Primary ciliary dyskinesia is characterized by ciliary dysmotility and the accumulation of thick secretions in the airways that obstruct air and gas exchange. Neonatal clinicians should know that while PCD is definitively diagnosed in infancy or early childhood, findings suspicious for PCD should be communicated to primary care providers at discharge from the hospital to facilitate timely subspecialty involvement, diagnosis, and treatment. This article will present a case report of a term newborn with SI totalis who was later diagnosed with PCD. We will discuss epidemiology, pathophysiology, clinical manifestations, and diagnostics, followed by management strategies. Additionally, we discuss the outpatient needs and lifespan implications. [ABSTRACT FROM AUTHOR]

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is a rare inherited disorder characterized by progressive disintegration as well as calcification of elastic tissue, resulting in cutaneous, ophthalmic, cardiovascular and other systemic abnormalities. It is an autosomal recessive condition caused by alterations in the ABCC6 gene. We report two cases of pseudoxanthoma elasticum with varying degrees of cutaneous and systemic manifestations of the disease. Both patients had characteristic histopathological changes on skin biopsies and fulfilled the diagnostic criteria for definite PXE. The goal is to demonstrate diverse clinical facets of the disease and to emphasize clinical clues for prompt diagnosis in order to minimize the associated complications. [ABSTRACT FROM AUTHOR]

Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an extremely rare, autosomal recessive neurodegenerative disorder. It is caused by biallelic pathogenic variants in the ADPRS gene, which encodes an enzyme involved in DNA repair, and is characterized by exacerbations in relation to physical or emotional stress, and febrile illness. We report a 24-year-old female, who was compound heterozygous for two novel pathogenic variants revealed by whole exome sequencing. Additionally, we summarize the published cases of CONDSIAS. In our patient, onset of symptoms occurred at 5 years of age and consisted of episodes of truncal dystonic posturing, followed half a year later by sudden diplopia, dizziness, ataxia, and gait instability. Progressive hearing loss, urinary urgency, and thoracic kyphoscoliosis ensued. Present neurological examination revealed dysarthria, facial mini-myoclonus, muscle weakness and atrophy of hands and feet, leg spasticity with clonus, truncal and appendicular ataxia, and spastic-ataxic gait. Hybrid [18F]-fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) of the brain revealed cerebellar atrophy, particularly of the vermis, with corresponding hypometabolism. MRI of the spinal cord showed mild atrophy. After informed consent from the patient, we initiated experimental, off-label treatment with minocycline, a poly-ADP-polymerase (PARP) inhibitor, which has shown beneficial effects in a Drosophila fly model. The present case report expands the list of known pathogenic variants in CONDIAS and presents details of the clinical phenotype. Future studies will reveal whether PARP inhibition is an effective treatment strategy for CONDIAS. [ABSTRACT FROM AUTHOR]

Recently, an autosomal recessive subtype of connective tissue disorder within the spectrum of Ehlers–Danlos syndrome (EDS), named classical-like EDS type 2 (clEDS2), was identified. clEDS2 is associated with biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, specifically, affecting its aortic carboxypeptidase-like protein (ACLP) isoform. We described the 15th patient (13th family) diagnosed with clEDS2. This patient presented with notable similarities in phenotype to the documented cases, along with additional characteristics such as significant prematurity and short stature. An EDS sequencing panel-based analysis revealed homozygous AEBP1: NM_001129.5:c.2923del, p.Ala975Profs*22 likely pathogenic variants, and maternally inherited heterozygous COL11A1: NM_001854.4:c.1160A>G, p.Lys387Arg variant of uncertain significance in our patient. Upon comprehensive review of all previously reported clEDS2 patients, our patient exhibited the following overlapping phenotypes, including cutaneous features: hyperextensibility, atrophic scars/delayed wound healing (100%), easy bruising (100%), excessive skin (93%); skeletal features: generalized joint hypermobility (93%), pes planus (93%), dislocation/subluxation (93%); and cardiovascular features (86%). Our patient did not display symptoms of the critical complications reported in a few individuals, including superior mesenteric artery aneurysms and ruptures, aortic root aneurysm/dissection, spontaneous pneumothoraxes, and bowel ruptures. Together, this case expands the genetic and clinical phenotypic spectrum of AEBP1-related clEDS2. [ABSTRACT FROM AUTHOR]