Genotypic Spectrum Research Articles

Genetic and clinical spectrum of steroid-resistant nephrotic syndrome with nuclear pore gene mutation.

Steroid-resistant nephrotic syndrome (SRNS) is insensitive to steroid therapy and overwhelmingly progresses to kidney failure (KF), the known pathogenic genes of which include key subunits of the nuclear pore complex (NPC), a less-recognized contributor to glomerular podocyte injury. After analyzing their clinical characterizations and obtaining parental consent, whole-exome sequencing (WES) was performed on patientswith SRNS. Several nucleoporin (NUP) biallelic pathogenic variants were identified and further analyzed by cDNA-PCR sequencing from white cells of peripheral blood, minigene assay, immunohistochemical (IHC) staining, and electron microscopy (EM) ultrastructure observation of kidney biopsy, as well as multiple in silico prediction tools, including 3D protein modeling. Here, in six familieswith SRNS, we identified pathogenic mutations in NUP85/93/107/160 genes. Specifically, thepatient with NUP93mutation developed KF six months after diagnosis at 1year 2months. Two missense mutations, c.1655A > G and c.1604A > C, disrupted the protein stability of NUP93 by IHC staining of kidney biopsy. Ultrastructurally, the above mutations led to severe vacuolization and deformed nucleus in podocytes, torn and dissolved glomerular basement membrane, and diffuse foot process effacement. Thepatient with NUP85mutation reached chronic kidney disease (CKD)stage 3 after 4years follow-up, with exons 2-5 in-frame loss and a missense variant at c.511C > T, not affecting NUP85 expression but possibly weakened interaction with Seh1. Additionally, an extended endoplasmic reticulum (ER) tubule was readily observed under EM. Meanwhile, dilated ER was also found in twochildren with NUP160mutations (c.3330 delA and c.2407 G > A; c.2241 + 1 (IVS17) G > T and c.3656T > G), one of which has undergone kidney transplantation. Compound heterozygous variants in NUP107, c.1695 G > C and c.1360 C > T, were found in a 14-year-old girl initially diagnosed with CKDstage5, with the former variant causing exon 19 skipping and early translation termination. c.1311 + 1(IVS15) G > A and c.1790 C > T were identified in the second affected girl, with the former causing exon 15 skipping and an in-frame loss of aa417-438, which disrupted the stability of NUP107 and interaction with NUP133. Our findings expand the spectrum of phenotypes and genotypes of NUPs-associated SRNS and suggest its possible pathogenic mechanism in nuclear and ER homeostasis.

Genotyping as Part of Routine Clinical Care-The Outcomes for a Large Paediatric Vascular Anomaly Cohort.

We describe the phenotypic and genotypic spectrum of patients with vascular anomaly (VA) in a paediatric multi-disciplinary VA clinic. We measured the clinical utility of genotyping by comparing pre and posttest diagnosis and management. A 46-month retrospective analysis occurred for 250 patients offered genetic testing in the VA clinic. DNA was extracted from biopsied vascular lesions. The coding regions of 27 genes were amplified by multiplex PCR and sequenced with mean coverage depth ranging from 3005× to 66,320×, achieving >95% amplification with at least 500 reads. The limit of detection was approximately 1%. Germline confirmatory testing was arranged where phenotype and variant allele frequency (AF) were compatible with a heritable VA. A molecular diagnosis was identified for 191 of 250 (76%). A somatic cause for VA was confirmed for 70% and a germline cause for 6%. Genetic testing supported the clinical diagnosis for 55% of our patient group and revised the clinical diagnosis for 21%. For patients with a revised clinical diagnosis, a management change occurred for 62%. 33% of patients offered genetic testing for VA had a management change. 24% were referred for consideration of molecularly targeted therapy (MTT). Routine genotyping in paediatric VA improves diagnosis and management outcomes.

Gene Panel-based Genotyping of 279 Turkish Maturity-Onset Diabetes of the Young Patients from Eastern Anatolia

Objective: The aim of this study was to analyse the genotypic and clinical characteristics of Turkish patients with Maturity-onset Diabetes of the Young (MODY) in Eastern Anatolia in order to improve the understanding of the genetic diversity and clinical manifestations of MODY. The findings should help to improve the diagnosis and management of monogenic diabetes. Materials and Methods: This retrospective study included 279 patients with suspected MODY, selected for age at presentation, family history, no pancreas autoantibodies and minimal/no need for insulin. A next-generation sequencing (NGS) panel was used for genetic analysis. The panel included 15 different genes. Conclusion: In about 94% of the patients varants in GCK, HNF1A and HNF4A were detected.This study provides valuable insights into the genotypic and clinical spectrum of MODY in a Turkish population. The findings underscore the importance of comprehensive genetic testing and personalized approaches to optimize MODY diagnosis and treatment. The study emphasizes the crucial role of genetic testing in managing and treating MODY. Detailed analysis of genetic variations and clinical manifestations plays a crucial role in diagnosing and assessing MODY risks. The results may inform the development of personalized treatment approaches.

Clinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.

In this study, we described rare clinical manifestations and detected three novel variants in NF1, BRAF, and RIT1 genes. We propose that NGS technology enables the detection of variants in rare genes responsible for the etiology of RASopathies. The study, therefore, not only contributes to the existing literature but also expands the spectrum of genotype and phenotype of RASopathies. •RASopathies are a group of disorders caused by germline variants in genes involved in the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway. •These disorders, including Noonan syndrome (NS), Cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Legius syndrome, and Neurofibromatosis type 1 (NF1), share overlapping clinical features due to RAS/MAPK dysfunction. Molecular diagnosis of RASopathies is crucial for understanding the genetic basis and guiding clinical management, although the phenotype-genotype relationships remain incompletely defined. •This study provides new insights into the molecular and clinical characteristics of RASopathies by examining 149 patients from 146 families, with a focus on the genetic variants found in 24 RASopathy-related genes. Three novel variants were identified in the RIT1, BRAF, and NF1 genes, expanding the genetic spectrum of RASopathies. •Additionally, rare clinical findings, such as lymphangioma circumscriptum and corpus callosum thickness, were reported in patients with PTPN11 and SOS1 gene variations, respectively. These observations contribute new phenotypic data to the existing body of knowledge.

Novel Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of CNKSR2 in the Houge Type of X-Linked Syndromic Intellectual Development Disorder (MRXSHG).

The Houge type of X-linked syndromic intellectual developmental disorder (MRXSHG) encompasses a spectrum of neurodevelopmental disorders characterized by intellectual disability (ID), language/speech delay, attention issues, and epilepsy. These conditions arise from hemizygous or heterozygous deletions, along with point mutations, affecting CNKSR2, a gene located at Xp22.12. CNKSR2, also known as CNK2 or MAGUIN, functions as a synaptic scaffolding molecule within the neuronal postsynaptic density (PSD) of the central nervous system. It acts as a link connecting postsynaptic structural proteins, such as PSD95 and S-SCAM, by employing multiple functional domains crucial for synaptic signaling and protein-protein interactions. Predominantly expressed in dendrites, CNKSR2 is vital for dendritic spine morphogenesis in hippocampal neurons. Its loss-of-function variants result in reduced PSD size and impaired hippocampal development, affecting processes including neuronal proliferation, migration, and synaptogenesis. We present 15 patients including three from the MENA (Middle East and North Africa), a region with no documented mutations in CNKSR2. Each individual displays unique clinical presentations that encompass developmental delay, ID, language/speech delay, epilepsy, and autism. Genetic analyses revealed 14 distinct variants in CNKSR2, comprising five nonsense, three frameshift, two splice, and four missense variants, of which 13 are novel. The ACMG guidelines unanimously interpreted these 14 variants in 15 individuals as pathogenic, highlighting the detrimental impact of these CNKSR2 genetic alterations and confirming the molecular diagnosis of MRXSHG. Importantly, variants Ser767Phe and Ala827Pro may lead to proteasomal degradation or reduced PSD size, contributing to the neurodevelopmental phenotype. Furthermore, these two amino acids, along with another two affected by four missense variants, exhibit complete conservation in nine vertebrate species, illuminating their crucial role in the gene's functionality. Our study revealed unique new digital and brain phenotype, including pointed fingertips (fetal pads of fingertips), syndactyly, tapering fingers, and hippocampal atrophy. These novel clinical features in MRXSHG, combined with 13 novel variants, expand the phenotypic and genotypic spectra of MRXSHG associated with CNKSR2 mutations.

Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia.

Skeletal dysplasias are a clinically and genetically heterogeneous group of rare disorders. Studies from large cohorts are essential to provide insights into the disease epidemiology, phenotypic spectrum, and mutational profiles. Here we enumerate additional 248 Indians from 197 families with a skeletal dysplasia, following a similar study earlier. We achieved a clinical-molecular diagnosis in 145 families by targeted analysis in 37 and next generation sequencing (exomes and genomes) in 108 families that resulted in a diagnostic yield of 73.6% (145 of 197 families). We identified 149 causal variants, of which 85 were novel, across 73 genes. Eighty-one distinct monogenic forms of skeletal dysplasia were observed with a high proportion of autosomal recessive skeletal dysplasias (60%, 84 families). We observed consanguinity in 35% of the families. Lysosomal storage diseases with skeletal involvement, FGFR3-related skeletal dysplasia and disorders of bone mineralisation were most frequent in this cohort. We expand the phenotypic and genotypic spectrum of rarely reported conditions (RAB33B, TRIP11, NEPRO, RPL13, COL27A1, PTHR1, EXOC6B, PRKACA, FUZ and RSPRY1) and noted novel gene-disease relationships for PISD, BNIP1, TONSL, CCN2 and SCUBE3 related skeletal dysplasia. We successfully implemented genomic testing for skeletal dysplasia in clinical and research settings. Our study provides valuable information on the spectrum of skeletal dysplasia and disease-causing variants for Asian Indians.

A Homozygous MYH1 Variant Underlies Autosomal Recessive Isolated Recurrent Rhabdomyolysis.

Rhabdomyolysis is a severe condition involving the breakdown of skeletal muscle fibers, leading to the release of muscle components into the bloodstream, which can lead to potential complications such as acute kidney injury and electrolyte imbalances. The etiology of rhabdomyolysis is multifactorial, encompassing traumatic, exertional, metabolic, infectious, toxic, and genetic causes. Genetic causes, including variants in LPIN1, RYR1, and CACNA1S, are increasingly recognized as significant contributors to recurrent rhabdomyolysis. MYH1 has recently been identified as a candidate gene for recurrent rhabdomyolysis with limited evidence originating from a single patient. In this report, we describe a 35-year-old male, born to consanguineous parents, who presented with recurrent rhabdomyolysis attacks, beginning at age 28, characterized by muscle pain, weakness, and episodes of acute kidney injury requiring dialysis. During attacks, the patient exhibited remarkably elevated markers of muscle breakdown and mildly elevated creatine kinase levels between episodes. A muscle biopsy revealed non-specific myopathic changes. Exome sequencing analysis was carried out and revealed a novel homozygous variant (NM_005963.4: c.1825G>A [p.Val609Met]) in MYH1 segregating in a manner compatible with an autosomal recessive pattern. In summary, this case provides confirmatory support for the role of pathogenic MYH1 variants in the pathogenesis of recurrent rhabdomyolysis and emphasizes the importance of comprehensive genetic testing in patients with unexplained recurrent episodes of muscle breakdown. Further cases are necessary to fully elucidate the genotypic and phenotypic spectrum of MYH1-related muscle disorders.

Prevalence and phylogenetic analysis of cytomegalovirus (Orthoherpesviridae: <i>Cytomegalovirus: Cytomegalovirus humanbeta5</i>) genetic variants from children and immunocompromised patients in central Russia

Introduction. Cytomegalovirus (CMV) is a DNA-containing virus that is widespread worldwide and is of great importance in infectious pathology of children and adults. The aim of this study is to evaluate the prevalence of CMV among children and immunocompromised patients in the Nizhny Novgorod region (central Russia) and to perform a phylogenetic analysis of the identified strains. Materials and methods. DNA samples of CMV detected in frequently ill children and adult recipients of solid organs were studied. The genetic diversity of CMV was assessed for two variable genes: UL55(gB) and UL73(gN), using NGS technology on the Illumina platform. Phylogenetic trees were constructed in the MEGA X program, the reliability of the cluster topology on the trees was confirmed using the rapid bootstrap method based on the generation of 500 pseudo-replicas. Results. Circulation of 5 CMV genotypes by gene UL55(gB) and 5 genotypes by gene UL73(gN) was established in the territory of the Nizhny Novgorod region. While genotypes gB1 and gB2 dominated both in children and in adults, genotype gB5 was detected only in children. The spectrum of gN genotypes was more diverse: genotypes gN4a and gN3b prevailed in children, and gN1 and gN4b genotypes were predominant in adults. The obtained results allowed us to establish the similarity of the landscape of CMV genotypes circulating in Russia (Nizhny Novgorod region), Brazil, China and the USA. Conclusion. The obtained data indicate the similarity of the landscape of CMV genotypes circulating in Russia (Nizhny Novgorod region), Brazil, China and the USA: in children, the predominant genotypes are gB1 (40.0%), gB2 (33.3%), gN4a (42.8%), and gN3b (28.6%), while in adults (recipients of solid organs) genotypes gB1 (37.5%), gB2 (37.5%), gN1 (26.3%), and gN4b (26.3%) are prevailed.

Unveiling New Clinical and Genetic Insights in Ultra-Rare Intellectual Disability Phenotypes: A Study of a Turkish Cohort.

Intellectual disability (ID) is defined as a severe impairment in reasoning, learning, and problem-solving abilities along with adaptive behavior that occurs before the age of 18 years. The present study aimed to present the clinical and genetic data of a cohort of Turkish pediatric patients diagnosed with the ultrarare (which only up to 20 cases having been reported in the relevant literature thus far) ID phenotype. A total of 29 patients from 26 different families, who were diagnosed with ultrarare ID upon whole exome sequencing (WES) analysis, were included in the study. Of the patients included in the study, 18 (62%) were male and 11 (38%) were female. There was consanguinity between parents in 16 families (55%). With respect to the ID phenotype, three families had cases with a similar phenotype, while 23 families (88%) had sporadic cases. Upon molecular analysis, 28 different variations in 23 different genes were noted. Of the variations detected, 15 were missense, 6 nonsense, 4 frameshift, 2 splice-site, and 1 gross exonic deletion. Nine (32%) variations were novel among the detected variations. This study summarized the clinical and genetic features of 23 different ultrarare ID phenotypes by means of WES study, including copy number variations (CNVs) analysis. Novel clinical and genetic findings in the present study contribute to a better understanding of the genotypic and phenotypic spectrum. The effects of some rare variations on protein structure were revealed by means of in silico modeling. Newly described cases with ultrarare phenotypes help achieve a clearer description of the clinical and genetic manifestations of the syndromes and gain a better understanding of the molecular mechanisms.

Expanding the Clinical and Mutational Spectrum of Biallelic POC1A Variants: Characterization of Four Patients and a Comprehensive Review of POC1A-Related Phenotypes.

SOFT syndrome (SOFTS) is an autosomal recessive disorder caused by biallelic POC1A variants, characterized by short stature, distinctive facial features, onychodysplasia, and hypotrichosis. To date, 21 pathogenic POC1A variants have been reported in 26 families. This study aims to broaden the phenotypic and genotypic spectrum of SOFTS with emphasis on the long-term effects of growth hormone (GH) therapy. We report four unrelated patients with three homozygous POC1A variants and demonstrate the transcriptional effects of two canonical splicing variants. All four patients had severe growth retardation, sparse hair/eyebrows, high/prominent forehead, long/triangular face, prominent nose, short middle/distal phalanges, puffy/tapering fingers, and prominent heels. Endocrine abnormalities included insulin resistance and impaired glucose tolerance, dyslipidemia, GH deficiency, central hypothyroidism, and precocious puberty. Two patients treated long-term with recombinant human GH showed insufficient responses. We also provide an extensive review of 43 cases including those we report, contributing to a better understanding of the full clinical and endocrinological spectrum of SOFTS.

Mutational and clinical spectrum of myofibrillar myopathy in one center from China

Background: Myofibrillar myopathy (MFM) is a heterogeneous group of neuromuscular disorders characterized by degeneration of Z-disk and disintegration of myofibrils. OBJECTIVE: We aimed to analyze the mutational spectrum and phenotypic features of MFM in China. Methods: We used targeted next generation sequencing (NGS) to identify causative mutations in 39 MFM patients with confirmed myopathological diagnosis. Results: The results showed that variants were found in six MFM-associated genes, including DES, FLNC, BAG3, MYOT, TTN and DNAJB6, in 28 (71.7%), 3 (7.7%), 3 (7.7%), 1 (2.6%), 3 (7.7%), and 1 (2.6%), respectively. Of the total 26 variants identified, 19 were reported previously and 7 were novel variants. Missense variant (80.0%) was the most common mutant type of DES. P209L was the hotspot mutation of BAG3 while no obvious hotspot mutation was found of DES. Clinically, distal and proximal weakness were observed in 64.1% and 35.9% patients. Arrythmia and peripheral neuropathy were the most common combined symptoms of desminopathy and BAG3opathy, respectively. Pathologically, rimmed vacuoles (RVs) were present in different genetic type of MFM. Giant axonal nerve fiber was found in BAG3-releated MFM patient. Conlusion: We concluded that MFM showed a highly variable genetic spectrum, with DES as the most frequent causative gene followed by FLNC, BAG3 and TTN. This study expanded the genotypic and phenotypic spectrum of MFM among Chinese cohort.

Phenotypic Differentiation Within the aac(6') Aminoglycoside Resistance Gene Family Suggests a Novel Subtype IV of Contemporary Clinical Relevance.

Whole genome sequencing of clinical bacterial isolates holds promise in predicting their susceptibility to antibiotic therapy, based on a detailed understanding of the phenotypic manifestation of genotypic variation. The aac(6') aminoglycoside acetyltransferase gene family is the most abundant aminoglycoside resistance determinant encountered in clinical practice. A variety of AAC(6') isozymes have been described, suggesting a phenotypic distinction between subtype I, conferring resistance to amikacin (AMK), and subtype II, conferring resistance to gentamicin (GEN) instead. However, the epidemiology and thus clinical relevance of the various and diverse isozymes and their phenotypic distinction demand systematic and contemporary re-assessment to reliably predict bacterial susceptibility to aminoglycoside antibiotics. We analyzed the resistance gene annotations of 657,603 clinical bacterial isolates to assess the prevalence and diversity of aac(6') genes. Seventeen unique aac(6') amino acid sequences were cloned and expressed under defined promoter control in otherwise isogenic E. coli cells for phenotypic analysis with twenty distinct aminoglycoside antibiotics. A panel of clinical isolates was analyzed for the genotype-phenotype correlation of aac(6'). An aac(6') resistance gene annotation was found in 139,236 (21.2%) of the clinical isolates analyzed. AMK resistance-conferring aac(6')-I genes dominated in Enterobacterales (28.5%). In Pseudomonas aeruginosa and Acinetobacter baumannii, a gene conferring the aac(6')-II phenotype but annotated as aac(6')-Ib4 was the most prevalent. None of the aac(6') genes were annotated as subtype III, but gene aac(6')-Ii identified in Gram-positive isolates displayed a subtype III phenotype. Genes that were annotated as aac(6')-Ib11 in Enterobacterales conferred resistance to both AMK and GEN, which we propose constitutes a novel subtype IV when applying established nomenclature. A phenotypic assessment facilitated structural re-assessment of the substrate promiscuity of AAC(6') enzymes. Our study provides the most comprehensive analysis of clinically relevant aac(6') gene sequence variations to date, providing new insights into a differentiated substrate promiscuity across the genotypic spectrum of this gene family, thus translating into a critical contribution towards the development of amino acid sequence-based in silico antimicrobial susceptibility testing (AST).

A rare case of myopathy with fatigability due to PYROXD1 variation

Introduction: Congenital myopathies are a group of heterogenous inherited muscle diseases. With advances in genetics, newer genes with novel features are being described. Pyridine nucleotide-disulfide oxidoreductase domain 1 ( PYROXD1) related myopathy is an ultrarare congenital myopathy. Only few cases have been reported worldwide till now. We report the first interesting case of PYROXD1 related myopathy from India. Methods: This is a retrospective study done from a quaternary neurology referral centre from southern India. All clinical, laboratory and electrophysiological data were collected from the medical records. Institutional ethics approval and informed consent from patient were obtained. Results: A 9 year-old-boy of non-consanguineous parentage presented with progressive fatigable proximo-distal weakness of upper and lower limbs with facial weakness from the age of 4 years. This was followed by chewing and swallowing difficulty. However speech was normal. There was profound proximal and distal joint hyperextensibility along with hip and ankle contractures. There was facial dysmorphism with high arched palate and retrognathism. Investigations showed normal serum creatine kinase levels. Nerve conduction studies showed axonal sensorimotor neuropathy. There was significant decremental response in tibialis anterior. Muscle biopsy showed both myopathic and neurogenic changes with novel findings of mitochondrial aggregates in subsarcolemmal and perinuclear regions. Next generation sequencing revealed a missense variant NM_024854.5:c.394C > T (NP_079130.2:p.Arg132Cys) of uncertain significance in exon 4 of PYROXD1 gene. Conclusion: This is the first report of PYROXD1 related myopathy from India. There were novel features of muscle fatigability, contractures, novel muscle biopsy features and a variant of uncertain significance expanding the phenotypic and genotypic spectrum of this rare myopathy.

Clinical spectrum and genetic variation of six patients with methylmalonic aciduria (MMA); a report from Iran

ObjectiveMethylmalonic acidemia (MMAs) is known as a severe, complex, and lethal disorder of methylmalonate and cobalamin. The patients with MMA may have developmental, neurological, and metabolic disorders such as liver disease. Here, we aim to evaluate 6 Iranian patients suspected to MMA disorder.Study designWe will provide genetic results, biochemical analysis and treatment for these patients. Liquid chromatography-tandem mass spectrometry (LC–MS/MS) and variant screening in probands by whole exome sequencing (WES) were performed.ResultsA total of six homozygous variants were identified, including five previously identified variants and one novel variant, in the two MMA-causing genes as follows: c.577G > C, c.290 + 69G > T, c.662T > A, c.290 + 69G > T of MMAB, and c.100dupA, c.394 C > T of MMACHC. Sanger sequencing confirmed the identified variants. Additionally, metabolomics data analysis reliably identified elevated C3 and MMA levels, as well as abnormalities in the amino acid profile, indicating the presence of pathogenic variants.ConclusionsOur findings expand the global spectrum of genotypes in MMA. While WES, combined with metabolomics and biochemical analysis, offers valuable insights for accurate diagnosis and subtyping of MMA, it is most beneficial in complex cases where clinical findings are unclear.

Genotype First Approach as a Diagnostic Strategy for Precision Medicine in Moroccan Families with Nephronophthisis

AbstractNephronophthisis is a group of autosomal recessive kidney diseases characterized by chronic tubulointerstitial abnormalities leading to kidney failure. The incidence of nephronophthisis varies globally, and its genetic heterogeneity presents significant difficulties in diagnosis. Herein, we present a molecular diagnosis of four unrelated Moroccan families fulfilling the clinical criteria of nephronophthisis. As first diagnosis step, screening for a homozygous NPHP1 gene deletion, the most common mutation, was performed by using multiplex polymerase chain reaction. Additionally, clinical exome sequencing was carried out on patients in whom no NPHP1 deletion was identified. Three novel pathogenic variants in NPHP1, INVS, and NPHP4 genes were identified and confirmed by Sanger sequencing in the proband and other family members. These variants are absent from genetic databases of patients and controls of Moroccan origin. The bioinformatics analysis classified these variants as pathogenic. Our findings expand the genotypic spectrum of nephronophthisis and highlight the importance of genetic testing in patients from low- and middle-income countries to obtain a precise diagnosis of nephronophthisis. This helps facilitate an appropriate and personalized genetic counseling and improves clinical outcomes for patients with this condition.

Childhood Familial Mediterranean Fever in the United States: Spectrum of Clinical Phenotypes and MEFV Genotypes in a Cohort From Southeast Michigan.

The aim of this study was to report the spectrum of Familial Mediterranean Fever (FMF) in children living in Southeast Michigan. We reviewed prerecorded data in medical records of FMF patients. Statistical analysis of the data included Fisher exact test, Pearson χ2 procedure, parametric independent samples t test, and parametric analysis of variance using SPSS Version 29.0, IBM Inc. The study included 29 males and 21 females. The mean age at presentation was 4.63 ± 3.66 years, and the mean time to diagnosis was 2.1 ± 2.18 years. A slight majority presented in the first 3 years of age (54%). Family history of FMF was reported in only 58% of patients. Clinical manifestations included fever (84%), gastrointestinal (84%), musculoskeletal (64%; including chronic arthritis, sacroiliitis, and nonbacterial osteomyelitis), chest (28%), cutaneous (14%), and other manifestations (16%). Fever without other manifestations was reported only in patients presenting at ≤3 years of age (p = 0.016), whereas older patients reported more gastrointestinal manifestations (p = 0.04). Reported MEFV variants included p.M694V (n = 26), p.V726A (n = 23), p.M694I (n = 13), and others (n = 10). Homozygote and compound heterozygote patients had more gastrointestinal manifestations (p < 0.001), whereas fever was more common in the heterozygote patients (p = 0.04). The mean follow-up period was 5.34 ± 4.13 years with no renal disease. We report the largest childhood FMF cohort in the United States. A negative family history should not preclude consideration of FMF as a cause of periodic fever. Recurrent fever can be the only manifestation, particularly in young patients with FMF. The absence of fever and chronic progressive musculoskeletal manifestations can uncommonly occur.

Co-occurrence of Charcot-Marie-Tooth disease type 1 and glomerulosclerosis in a patient with a de novo INF2 variant

BackgroundRenal disease is associated with Charcot-Marie-Tooth disease (CMT), a common inherited neurological disorder. Three forms of CMT have been identified: CMT1 of the demyelinating type, CMT2 of the axonal defect type, and intermediate type (Int-CMT). INF2 is an important target for variants that cause the complex symptoms of focal segmental glomerulosclerosis (FSGS) and CMT.Case presentationWe report the case of a 13-year-old female Chinese patient (born in 2011) with a rare co-occurrence of CMT1 and glomerulosclerosis (GS) (CMT1-GS). The patient presented with slowly progressive gait disorder with unsteadiness during walking, pes cavus, and kyphoscoliosis since the age of 1 year. Electrophysiological studies and brain magnetic resonance imaging revealed demyelinating features consistent with CMT1. At 12 years of age, she was hospitalised for hypertension and dizziness; her serum albumin was 27.9 g/L, serum creatinine was 87 μmol/L, estimated glomerular filtration rate was 88.6 mL/min, and 24-h urine protein was 4.95 g. A renal biopsy showed glomerulosclerosis. Renal function deteriorated further during the follow-up period, and she received a kidney transplant at the age of 13. Whole-exome sequencing identified a de novo heterozygous c.326T > G (p.Met109Arg) variant in exon 2 of INF2. The variant was classified as “pathogenic” according to the American College of Medical Genetics and Genomics criteria.ConclusionsWe describe a rare clinical phenotype of CMT1-GS associated with a de novo variant of INF2. Our findings expand the phenotypic and genotypic spectrums of INF2-associated disorders.

A rare ocular phenotype associated with oculofaciocardiodental syndrome

Abstract Oculofaciocardiodental syndrome (OFCD) is a rare genetic disease affecting the ocular, facial, cardiac, and dental systems. This report describes a rare ocular phenotype in a 6-year-old female child who presented with a history of bilateral whitish appearance in the eyes, nystagmus, photoaversion, and reduced best-corrected visual acuity since birth. Ocular examination revealed broad peripheral iridocorneal adhesions and iris atrophic holes, resembling Axenfeld–Rieger spectrum, apart from the usual microcornea and congenital cataract. Extraocular features included a history of recurrent respiratory tract infections and failure to thrive in the early neonatal period, acyanotic heart disease with a large atrial septal defect, inability to supinate the right forearm since birth, asymmetric limbs, and mild facial dysmorphism. Whole-exome sequencing revealed a pathogenic nonsense variant (c. 4540C&gt;T,p.Arg1514Ter) in BCOR gene. The BCOR gene, located on the X chromosome, is a zinc finger transcriptional repressor that plays a role in gene repression by interacting with DNA promoter regions and histone deacetylases. The precise mechanism by which the gene defect causes the ocular phenotype is poorly understood. The patient had features of anterior segment dysgenesis which has rarely been reported in OFCD. This report widens the genotypic spectrum of ASD and expands the phenotypic presentation of OFCD.

Expanding the genotypic and phenotypic spectrum of Egyptian children with maple syrup urine disease

Maple Syrup Urine Disease (MSUD, OMIM# 248600) is an autosomal recessive inborn error of metabolism characterized by elevated branched chain amino acids (BCAA) leucine/isoleucine and valine in blood of affected children. The phenotypic and genotypic spectrum of MSUD is largely unreported in Egypt. We recruited ten patients (4 males/6 females, 2weeks-12years) from nine unrelated families with clinical and biochemical evidence of MSUD. We performed Sanger sequencing for the three most-commonly responsible genes: BCKDHA, BCKDHB and DBT and conducted exome sequencing for unresolved cases. Through Sanger sequencing, we detected eight homozygous pathogenic/likely pathogenic variants (four in BCKDHB, three in BCKDHA and one in DBT gene) in eight different families. The proband of family VI, who had no significant genetic findings by Sanger, had a peculiar phenotype and atypical radiological findings. His exome sequencing revealed a previously reported homozygous likely pathogenic variant in the RARS2 gene (NM_020320.5:c.1026G > A;p.(Met342Ile)) causing the mitochondrial-encephalopathy disorder pontocerebellar hypoplasia, type 6 (OMIM# 611523). Furthermore, the copy-number-variant analysis of the exome data revealed a biallelic duplication affecting exons 2–6 of the BCKDHB gene (GRCh38: Chr.6-g.80127496:80171441dup) evaluated as variant of uncertain significance but expected to cause a breakpoint and may disrupt gene function, which can explain the markedly elevated BCAA levels in the patient’s blood. In conclusion, we expanded the genotypic and phenotypic spectrum of the disease and showed that aggressive intervention with specific treatment in the first few days of life resulted in normal development even in a developing country setting. Inclusion of MSUD in the national newborn screening program in Egypt is highly recommended.

De Novo Missense Mutation in FREM1 Identified in a Chinese Patient with Comorbid Congenital Microtia and Pulmonary Hypoplasia.

Cases of microtia combined with pulmonary hypoplasia are occasionally in clinics, and its genetic etiology has so far proved inconclusive. Here, aiming to contribute to a better understanding of microtia-related comorbid respiratory anomalies, the authors provide a clinical and genetic description of a rare trio family of which the son suffers combined deformities of right microtia, left pulmonary hypoplasia, and dextrocardia using whole-genome sequence (WGS). A novel potential pathologic compound heterozygosity in the FREM1 gene was identified and validated by the trio and bioinformatics analysis. This case expands the FREM1 mutation genotype and phenotype spectrum, sheds light on the congenital deformities of microtia and pulmonary hypoplasia, and emphasizes the importance of the FREM1 gene in pulmonary and craniofacial development.