Recessive Pattern Of Inheritance Research Articles

Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan

BackgroundHereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis.MethodsFamilies from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen’s h.ResultsWES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies.ConclusionsThis study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families.

Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia.

Variation in the non-coding genome represents an understudied mechanism of disease and it remains challenging to predict if single nucleotide variants, small insertions and deletions, or structural variants in non-coding genomic regions will be detrimental. Our approach using complementary RNA-seq and targeted long-read DNA sequencing can prioritize identification of non-coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the SPAG1 gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern. RNA sequencing revealed reduced SPAG1 transcript levels and exclusive allele specific expression of the known pathogenic allele, suggesting the presence of a non-coding variant on the second allele that impacts transcription. Targeted long-read DNA sequencing identified a heterozygous 3 kilobase deletion of the 5' untranslated region of SPAG1, overlapping the promoter and first non-coding exon. This non-coding deletion was missed by whole exome sequencing and gene-specific deletion/duplication analysis, highlighting the importance of investigating the non-coding genome in patients with "missing" disease-causing variation. This paradigm demonstrates the utility of both RNA and long-read DNA sequencing in identifying pathogenic non-coding variants in patients with unexplained genetic disease.

The unlikely combination: Anderson-Fabry disease and congenital dyserythropoietic anemia type II in a pediatric patient.

Anderson-Fabry disease, a rare X-linked lysosomal disorder, and congenital dyserythropoietic anemia (CDA) Type II, an autosomal recessive condition, both have distinct inheritance patterns. Their co-occurrence is extremely rare, never been reported before. Therefore, screening is crucial for early management, and families should seek genetic counseling for children showing unusual presentations. Anderson-Fabry disease (AFD) is a rare condition, characterized by a lysosomal storage disorder affecting lipid storage. It manifests in two forms: classic (early-onset) and nonclassic (late-onset). Conversely, congenital dyserythropoietic anemia (CDA) is a rare blood disorder caused by ineffective erythropoiesis, which results in the production of abnormal erythroblasts during the maturation of red blood cells, with CDA type II being the most frequent type. Both disorders have well-understood pathophysiologies, yet they are genetically distinct. AFD is inherited in an X-linked manner, whereas CDA type II follows an autosomal recessive pattern of inheritance. Although both AFD and CDA type II have been reported separately in the literature. The co-existence for both AFD and CDA type II has not been reported. We describe a 10-year-old boy, with both which is believed to be the first documented case.

DNAH17 deficiency causes disruption in the assembly and docking of sperm flagellar ODAs but not total fertilization failure after ICSI

Research questionAre there other variants in DNAH17 related to male infertility? What is the correlation between total fertilization failure and DNAH17 deficiency? DesignWhole-exome sequencing and Sanger sequencing were performed in a cohort of 75 Chinese patients with MMAF to identify potential novel gene variants. Papanicolaou staining and electron microscopy were employed to observe sperm morphology and ultrastructure. Proteomic analysis and comprehensive functional analysis were performed to elucidate the relationship between DNAH17 deficiency and total fertilization failure at the molecular level. ResultsTen novel variants in DNAH17 were identified in five unrelated families with six infertile males. These identified variants exhibited an autosomal recessive inheritance pattern and caused the deficiency of DNAH17 in sperm. Papanicolaou staining and electron microscopy demonstrated typical MMAF characteristics and deformations in flagellar ultrastructure of DNAH17-deficient sperm. Furthermore, our comprehensive functional analysis revealed that DNAH17 deficiency impaired the assembly and docking of ODAs, affected the acrosome reaction, and disrupted mitochondrial function. Interestingly, the fertilization-related proteins such as ACTL7A and PICK1 were normal, while reduced yet ≥30% PLCζ levels were detected, implying an indirect correlation between DNAH17 deficiency and total fertilization failure. Moreover, four of the affected couples got transferable embryos successfully through intracytoplasmic sperm injection (ICSI) without artificial oocyte activation (AOA). ConclusionsOur findings significantly broaden the variant spectrum of DNAH17 and illuminate the complex molecular basis of male infertility associated with DNAH17 deficiency, particularly its heterogeneous impact on fertilization. The favourable fertility outcomes of ICSI will provide vital insights for genetic diagnosis and counselling in males affected by MMAF.

N-glycoproteomic and proteomic alterations in SRD5A3-deficient fibroblasts.

SRD5A3-CDG is a congenital disorder of glycosylation (CDG) resulting from pathogenic variants in SRD5A3 and follows an autosomal recessive inheritance pattern. The enzyme encoded by SRD5A3, polyprenal reductase, plays a crucial role in synthesizing lipid precursors essential for N-linked glycosylation. Despite insights from functional studies into its enzymatic function, there remains a gap in understanding global changes in patient cells. We sought to identify N-glycoproteomic and proteomic signatures specific to SRD5A3-CDG, potentially aiding in biomarker discovery and advancing our understanding of disease mechanisms. Using tandem mass tag (TMT)-based relative quantitation, we analyzed fibroblasts derived from five patients along with control fibroblasts. N-glycoproteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 3,047 glycopeptides with 544 unique N-glycosylation sites from 276 glycoproteins. Of these, 418 glycopeptides showed statistically significant changes with 379 glycopeptides decreased (P<0.05) in SRD5A3-CDG patient-derived samples. These included high mannose, complex and hybrid glycan-bearing glycopeptides. High mannose glycopeptides from protocadherin Fat 4 and integrin alpha-11 and complex glycopeptides from CD55 were among the most significantly decreased glycopeptides. Proteomics analysis led to the identification of 5,933 proteins, of which 873 proteins showed statistically significant changes. Decreased proteins included cell surface glycoproteins, various mitochondrial protein populations and proteins involved in the N-glycosylation pathway. Lysosomal proteins such as N-acetylglucosamine-6-sulfatase and procathepsin-L also showed reduced levels of phosphorylated mannose-containing glycopeptides. Our findings point to disruptions in glycosylation pathways as well as energy metabolism and lysosomal functions in SRD5A3-CDG, providing clues to improved understanding and management of patients with this disorder.

A comprehensive review of Alport syndrome: definition, pathophysiology, clinical manifestations, and diagnostic considerations.

Alport syndrome, a rare genetic disorder affecting around 1 in 50,000 individuals, primarily presents as microscopic hematuria and chronic kidney disease (CKD) with associated extrarenal complications. The Alport syndrome results from mutations in COL4A3, COL4A4, and COL4A5 genes, disrupting the formation of the α3-α4-α5 chain in the collagen IV network. The etiology involves X chromosome-related, autosomal dominant, autosomal recessive, and digenic inheritance patterns. The disease primarily manifests as kidney involvement, featuring persistent hematuria, proteinuria, and a progressive decline in renal function. Hearing loss, ocular abnormalities, and extrarenal manifestations further contribute to its complexity. Genotype-phenotype correlations are relatively evident, with distinct presentations in X-linked, autosomal recessive, and autosomal dominant cases. Diagnosis relies on urinalysis, histologic examination, and genetic testing with advancements in next-generation sequencing aiding identification. Although no specific treatment exists, early diagnosis improves outcomes, emphasizing the importance of genetic testing for prognosis and familial screening. The purpose of this review is to advance knowledge and enhance understanding of Alport syndrome.

Genetic profile of progressive myoclonic epilepsy in Mali reveals novel findings.

Progressive myoclonic epilepsy (PME) is a group of neurological disorders characterized by recurrent myoclonic seizures with progressive neurological deterioration. We investigated the genetics of three unrelated patients with PME from Mali, a country in sub-Saharan Africa highly underrepresented in genetic and genomic research. Participants were carefully examined and phenotyped. DNA was obtained for genetic analysis including whole exome sequencing (WES). In silico prediction tools and ACMG criteria were used to assess the deleteriousness of putative candidate variants. Pedigree analysis suggests autosomal recessive inheritance patterns for one family and sporadic forms of PME for the two other cases. WES identified novel homozygous missense variants in all the three patients, one each for NHLRC1, EPM2A, and NEU1. The sequence variants segregated with PME in each family and in silico studies including protein 3D structures, CADD scores and ACMG criteria suggested that they were damaging. PME is a group of clinically heterogeneous neurological disorders. Most reported cases in the literature are from European background with only a few cases described in North Africa. We report here novel pathogenic variants in three different genes causing PME phenotypes in three unrelated Malian patients, suggesting that genetic studies of underrepresented populations may expand the genetic epidemiology of PME. These findings also emphasize the need for inclusive genetic research to ensure a more targeted diagnostic and therapeutic approaches for diverse patient populations.

Primary ciliary dyskinesia: a case report of double DNAH11 mutant alleles

Primary ciliary dyskinesia (PCD), a rare disorder, is genetically varied. Mutations in proteins involved in the structure, function, or assembly of cilia are known to determine situs inversus, male infertility, and chronic destructive airway disease. PCD is inherited by an autosomal recessive pattern of inheritance in most cases. Nonetheless, patterns of autosomal dominant and X-linked inheritance have been mentioned. A history of recurrent upper and lower respiratory tract infections raised clinical suspicion of primary ciliary dyskinesia in a 10-year-old patient. Genetic tests were performed using next-generation sequencing technology (Illumina NextGen) with the multiplex ligation-dependent probe amplification technique for primary ciliopathies and syndromes subject to differential diagnosis. Genetic testing identified two pathogenic variants, not previously associated with a case report in the literature, c.7727A&gt;G (p.Asp2576Gly) and c.8578G&gt;A (p.Gly2860Ser), within the DNAH11 gene, which is associated with autosomal recessive PCD. The result also reported mutations in other genes involved in autosomal recessive PCD (DNAH8, DNAH9 and ZMYND10), which were classified as variants with uncertain clinical significance. Transmission electron microscopy of respiratory cilia and nasal nitric oxide measurement cannot be used to diagnose PCD in patients with DNAH11 mutations because the structure of cilia is normal, and the levels of NO are not constantly low. High-speed video microscopy analysis can be helpful because DNAH11 mutations cause a distinct phenotype of PCD. Nevertheless, the mutation analysis of various PCD-causing genes remains the easiest to conduct and with good results. Genetic research on PCD has identified a number of significant ciliary genes in recent years, offering fresh perspectives on the molecular processes underlying cilia assembly and function. This facilitates the development of new methods for the diagnosis, prevention, and treatment of PCD. However, because it is a highly complex and heterogeneous disease, the field of gene diagnosis and therapy in PCD is still in its infancy.

McArdle's Disease: A Differential Diagnosis of Metabolic Myopathies.

McArdle's disease, also known as glycogen storage disease type V or McArdle syndrome, is a pure muscle myopathy with an autosomal recessive inheritance pattern. It is caused by mutations in the gene that encodes muscle phosphorylase. Symptoms typically begin in late adolescence or early adulthood, presenting as exercise intolerance. This review focuses on the diagnosis of McArdle's disease, initially manifesting as a clinical picture of rhabdomyolysis in an 18-year-old male patient with a history of minor thalassemia who had been followed in pediatric consultation since age three for failure to thrive. After excluding common causes such as alcohol consumption, drug use, traumatic muscle compression, and other conditions, the diagnosis of McArdle's disease was considered. The diagnosis was supported by laboratory tests showing myoglobinuria and elevated creatine kinase levels, as well as the absence of increased serum lactate following ischemic exercise. Genetic testing confirmed the presence of mutations in the PYGM gene, corroborating the diagnosis. Treatment includes administering a diet rich in slow-absorbing carbohydrates, regular low-intensity physical exercise, and, in some cases, supplementation with vitamin B6 and creatine. The prognosis is generally favorable with proper disease management, although vigorous exercise should be avoided to prevent complications such as severe muscle injury and rhabdomyolysis. Although McArdle's disease is a rare condition, it is likely underdiagnosed. Ideally, it should be considered in the differential diagnosis of rhabdomyolysis in all patients with symptoms of exercise intolerance and/or recurrent myoglobinuria.

Genetic Basis of Hearing Loss in Mongolian Patients: A Next-Generation Sequencing Study.

The genetic landscape of sensorineural hearing impairment (SNHI) varies across populations. In Mongolia, previous studies have shown a lower prevalence of GJB2 mutations and a higher frequency of variants in other deafness-related genes. This study aimed to investigate the genetic variants associated with idiopathic SNHI in Mongolian patients. We utilized the next-generation sequencing for investigating the causative mutations in 99 Mongolian patients with SNHI. We identified pathogenic variants in 53 of the 99 SNHI patients (54%), with SLC26A4 being the most frequently mutated gene. The c.919-2A>G variant in SLC26A4 was the most prevalent, accounting for 46.2% of the mutant alleles. In addition, we identified 19 other known and 21 novel mutations in a total of 21 SNHI genes in autosomal recessive or dominant inheritance patterns. Our findings expand the understanding of the genetic landscape of SNHI in Mongolia and highlight the importance of considering population-specific variations in genetic testing and counseling for SNHI.

Identification of novel likely pathogenic variant in CDH23 causing non-syndromic hearing loss, and a novel variant in OTOGL in an extended Iranian family

BackgroundSensorineural hearing loss (SNHL) is a clinically and genetically heterogeneous group of disorders of the auditory system. SNHL can occur as a symptom in more than 400 syndromes, and mutations in more than 150 genes can lead to SNHL. Mutations in the GJB2 and GJB6 genes are among the most common causes of SNHL worldwide. Mutations in Cadherin 23 (CDH23) can cause Usher syndrome and/or non-syndromic hearing loss (NSHL).Material and methodsIn this study, the Whole Exome Sequencing (WES) was used to detect the cause of hearing loss in a large consanguineous Iranian family with two patients. All family members underwent a thorough Genotype–phenotype correlation assessment and co-segregation analysis to understand the inheritance pattern within the family. The candidate variants were further confirmed by Sanger sequencing. In addition, in silico analysis was performed to predict the functional impact of the variants; the interpretation of the variants was performed in accordance with the American College of Medical Genetics (ACMG) guidelines.ResultsWES results identified two novel variants, a homozygous missense variant in CDH23 (c.2961T > G) and a heterozygous splice site variant in OTOGL that was compatible with the autosomal recessive pattern of inheritance. Bioinformatics studies confirmed the pathogenic effects of novel variants. The c.2961T > G variant was classified as likely pathogenic.ConclusionsThe novel identified variant in the CDH23 was the cause of congenital profound progressive form of HL. Samples were not available from the second family to distinguish which variant is responsible for the molecular pathology of the disease. Further studies and functional examinations are suggested for investigating the role of OTOGL: c. 1863-1G > T in deafness.

Mutation spectrum of Tyrosinemia type I in Iran, A retrospective cohort study

Hereditary Tyrosinemia Type 1 (HT1) is a genetic disorder characterized by an autosomal recessive inheritance pattern, caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, which results in a deficiency of fumarylacetoacetase. In our study, we identified a total of 15 mutations, including 12 newly discovered and 3 previously reported pathogenic mutations, in a cohort of 19 Iranian patients with the acute form of HT1. Out of the 12 novel variants identified, 11 were missense variants: p.Asp126His, p.Gln75Glu, p.Leu385Pro, p.Ser92Thr, p.Leu96Arg, p.Val167Glu, p.Ala94Asp, p.Gly353Trp, p.Ser164Pro, p.Glu86His and p.Ala163Pro. Additionally, there was one nonsense variant, p.Try244X, that had not been previously reported. Interestingly, the Arg237X variant was found to be particularly prevalent in this study. Notably, three exons, namely exons 9, 3, and 6, exhibited a higher frequency of mutations. All of the identified variants are presumed to result in loss of function, impacting the clinical signs, disease progression, increasing tyrosine level, and the specific location of the mutation. Our study has provided valuable insights into the mutation spectrum of variants associated with HT1 disease which is reported for the first time from Iran. This information can facilitate the development of targeted mutation screening protocols, focusing on the most prevalent mutations within specific regions or ethnic groups.

Bi-allelic variants in COQ8B, a gene involved in the biosynthesis of coenzyme Q10, lead to non-syndromic retinitis pigmentosa

Retinitis pigmentosa (RP) is a Mendelian disease characterized by gradual loss of vision, due to the progressive degeneration of retinal cells. Genetically, it is highly heterogeneous, with pathogenic variants identified in more than 100 genes so far. Following a large-scale sequencing screening, we identified five individuals (four families) with recessive and non-syndromic RP, carrying as well bi-allelic DNA changes in COQ8B, a gene involved in the biosynthesis of coenzyme Q10. Specifically, we detected compound heterozygous assortments of five disease-causing variants (c.187C>T [p.Arg63Trp], c.566G>A [p.Trp189Ter], c.1156G>A [p.Asp386Asn], c.1324G>A [p.Val442Met], and c.1560G>A [p.Trp520Ter]), all segregating with disease according to a recessive pattern of inheritance. Cell-based analysis of recombinant proteins deriving from these genotypes, performed by target engagement assays, showed in all cases a significant decrease in ligand-protein interaction compared to the wild type. Our results indicate that variants in COQ8B lead to recessive non-syndromic RP, possibly by impairing the biosynthesis of coenzyme Q10, a key component of oxidative phosphorylation in the mitochondria.

Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy.

Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.

Hearing loss secondary to variants in the OTOF gene

ObjectiveGenetic variants in the OTOF gene are responsible for non-syndromic hearing loss with an autosomal recessive inheritance pattern. The objective of our work was to evaluate the clinical characteristics of patients with biallelic pathogenic variants in OTOF and their evolution after treatment. MethodsA cohort of 124 patients with prelingual hearing loss, studied from 1996 to 2023, was included in this study. A genetic analysis was conducted to identify the type and frequency of variants in the OTOF gene and their relation to the clinical characteristics of the patients. ResultsThe homozygous p. Gln829* variant in the OTOF gene was detected in 3 probands (2.4 %) of a group of 124 individuals with prelingual hearing loss. Another 6 family members to a total of 9 individuals were finally included. All presented with severe/profound bilateral sensorineural hearing loss of congenital onset. Three of these individuals were diagnosed with auditory neuropathy spectrum disorder. One individual passed the OAE test during the screening program, and since he did not have risk factors for hearing loss that would warrant ABR testing, this led to a delay in his hearing loss diagnosis. Four individuals underwent cochlear implants (three bilateral) with good functional outcomes in three of them. However, in 17 familial cases with heterozygous variants, either no hearing loss was observed or it was within the expected range for their age. ConclusionsHearing loss secondary to the p.Gln829* variant of the OTOF gene is relatively rare in our medical area. Its presence in homozygosity is the cause of severe/profound bilateral prelingual sensorineural hearing loss, responsible for auditory neuropathy with a good response to cochlear implantation.

Etiologic Diagnosis of Genetic Hearing Loss in an Ethnically Diverse Deafness Cohort.

Hearing loss is a common sensory disorder that impacts patients across the lifespan. Many genetic variants have been identified that contribute to non-syndromic hearing loss. Yet, genetic testing is not routinely administered when hearing loss is diagnosed, particularly in adults. In this study, genetic testing was completed in patients with known hearing loss. A total of 104 patients who were evaluated for hearing loss were enrolled and received genetic testing. Of those 104 patients, 39 had available genetic testing, 20 had one missing allele, and 45 yielded no genetic diagnosis. Of the 39 cases with genetic testing data, 24 were simplex cases, and 15 were multiplex cases. A majority of patients presented with an autosomal recessive inheritance pattern (n = 32), 26 of whom presented with congenital hearing loss. 38% of cases were positive for GJB2 mutation with c.35delG being the most common pathogenic variant. These findings are consistent with previous literature suggesting GJB2 mutations are the most common causes of non-syndromic hearing loss. Given the frequency of genetic variants in patients with hearing loss, genetic testing should be considered a routine part of the hearing loss work-up, particularly as gene therapies are studied and become more widely available. Many genetic variants have been identified that contribute to non-syndromic hearing loss. Given the frequency of genetic variants in patients with hearing loss, genetic testing should be considered a routine part of the hearing loss work-up.

The prevalence of SMN gene deletion/duplication in spinal muscular atrophy families referred to neuro-genetic centers of Mashhad, Iran

BackgroundSpinal muscular atrophy (SMA) is a group of motor neuron diseases. In 95% of SMA patients, the telomeric copy of the SMN gene (SMN1) is homozygously deleted. Due to the autosomal recessive pattern of SMA inheritance, individuals with a family history of SMA are at risk of being carriers. A total of 622 individuals from SMA families, including parents, siblings, and first, second, and third-degree relatives, were recruited to the neuro-genetic clinic of Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. SMA cases and suspected carriers were referred to the genetic laboratory. Pregnant women underwent amniocentesis and chorionic villi sampling at 12–14 gestational weeks. RFLP-PCR and real-time PCR were performed for symptomatic and asymptomatic individuals (possible carriers), respectively. RFLP and real-time PCR were performed for amniotic fluid and chorionic villi samples.ResultsThe study enrolled 622 subjects from SMA-affected families, including 159 fetuses and 463 non-fetuses. Two samples were missing. A total of 268 individuals (43.2%) were healthy (wild type), 187 individuals (30.1%) were heterozygous for exon deletion of SMN1, and 143 individuals (23%) were homozygous for exon deletion of SMN1. Four individuals (0.6%) showed three copies of the SMN1 gene.ConclusionThe frequency of carriers with two SMN1 copies on a single chromosome (cis) was estimated at 2.9% (18/622), and the total rate of carriers was approximately 21.8%. Considering the high rate of SMA carriers in this study, genetic counseling and definitive prenatal diagnosis are of utmost importance for reducing the psychosocial burden of the SMA disease among Iranian families.

An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy.

Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD, are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient's muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis.

Pathogenic relationship between phenotypes of ARPKD and novel compound heterozygous mutations of PKHD1.

To investigate whether the novel mutation of PKHD1 could cause polycystic kidney disease by affecting splicing with a recessive inheritance pattern. A nonconsanguineous Chinese couple with two recurrent pregnancies showed fetal enlarged echogenic polycystic kidney and oligoamnios were recruited. Pedigree WES, minigene splicing assay experiment and following bioinformatics analysis were performed to verify the effects, and inheritance pattern of diseasing-causing mutations. WES revealed that both fetuses were identified as carrying the same novel mutation c.3592_3628 + 45del, p.? and c.11207T>C, p.(Ile3736Thr) in the PKHD1 gene (NM_138694.4), which inherited from the father and mother respectively. Both bioinformatic method prediction and minigene splicing assay experience results supported the mutation c.3592_3628 + 45del, p.? affects the splicing of the PKHD1 transcript, resulting in exon 31 skipping. Another missense mutation c.11207T>C, p.(Ile3736Thr) has a low frequency in populations and is predicted to be deleterious by bioinformatic methods. These findings provide a direct clinical and functional evidence that the truncating mutations of the PKHD1 gene could lead to more severe phenotypes, and cause ARPKD as a homozygous or compound heterozygous pattern. Our study broadens the variant spectrum of the PKHD1 gene and provides a basis for genetic counseling and diagnosis of ARPKD.

Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.

Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.