Congenital myasthenic syndrome (CMS) refers to a rare heterogeneous group of hereditary disorders characterized by fatigue and muscle weakness due to impairment in neuromuscular transmission. A total of 40 genes have bee...Congenital myasthenic syndrome (CMS) refers to a rare heterogeneous group of hereditary disorders characterized by fatigue and muscle weakness due to impairment in neuromuscular transmission. A total of 40 genes have been identified in the pathogenesis of CMSs. The study assessed 22 patients (14 females and 8 males) with CMS of childhood onset with their phenotypes and genotypes. Genetic analysis revealed variations in the following eight genes: CHRNE, DOK7, GFPT1, COLQ, SLC25A1, CHAT, MUSK, and MYO9A. Eight novel variations were detected involving SLC25A1, MUSK, DOK7, GFPT1, and CHRNE. The median age was 14 years (range: 0.5-67 years). The median age of onset of symptoms was 8 months (range: 0-16 years). The longest time after the onset of symptoms was 62 years. The most common initial symptoms were weakness of extremities (n = 9) and ptosis (n = 8). Respiratory symptoms were present in 11 patients (50%), which showed progression, multiphasic disease course, and amelioration in 45.4%, 18.1%, and 36.3% of patients, respectively. Motor symptoms showed a progressive worsening in 68.1%, stationary course in 13.6%, multiphasic disease course in 13.6%, and amelioration in 4.5% of patients. Thanks to next-generation sequencing, diagnoses of CMS have been increasing over the recent years; so has the number of novel variants.
The RAR-related orphan receptor alpha (RORA) gene encodes a nuclear receptor involved in transcriptional regulation, circadian rhythm, and neurodevelopment. Dominant RORA variants are associated with intellectual develop...The RAR-related orphan receptor alpha (RORA) gene encodes a nuclear receptor involved in transcriptional regulation, circadian rhythm, and neurodevelopment. Dominant RORA variants are associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia, yet the phenotypic spectrum remains poorly defined. We performed comprehensive genetic and clinical analyses in four individuals with RORA variants from three unrelated families, using whole exome sequencing and chromosomal microarray analysis. Identified variants were confirmed by Sanger sequencing. Genetic analyses revealed three distinct RORA variants: a 15q21.2-q22.2 deletion encompassing RORA , a de novo nonsense variant c.499C>T (p.Gln167*), and a novel heterozygous frameshift variant c.683_686del (p.Glu228Valfs*78) segregating within a family. Clinical findings ranged from severe neurodevelopmental delay and epilepsy to mild intellectual disability and behavioral abnormalities, demonstrating marked intrafamilial variability. Notably, the same frameshift variant presented with differing phenotypes in the family, indicating variable expressivity-the first such observation reported in RORA -related disorders. Our findings broaden the genotypic and phenotypic spectrum of RORA-related neurodevelopmental disorders. The observed intrafamilial variability highlights the complexity of RORA-associated pathogenesis and underscores the importance of considering variable expressivity in future genotype-phenotype studies.
A novel biallelic missense mutation (c.470A>T) in the STN1 gene is responsible for Coats Plus Syndrome.A novel biallelic missense mutation (c.470A>T) in the STN1 gene is responsible for Coats Plus Syndrome.
This study aimed to analyze the clinical phenotypes, treatment response, and related risk factors in children with epilepsy to improve diagnosis and prognosis, employing a retrospective-prospective cohort design involvin...This study aimed to analyze the clinical phenotypes, treatment response, and related risk factors in children with epilepsy to improve diagnosis and prognosis, employing a retrospective-prospective cohort design involving 848 children with non-acquired epilepsy who underwent genetic testing and were followed for 1-5 years to monitor treatment efficacy and development, with participants categorized into Gene-positive (n = 484) and Gene-negative (n = 364) groups for comparative analysis. Results showed that the Gene-negative group had a better treatment response than the Gene-positive group, and multivariate logistic analysis identified specific high-risk factors for poor treatment response in each group: febrile seizures history, delayed language development, concomitant congenital heart disease, and the use of ≥ 4 ASMs in the Gene-positive group, and comorbidities such as autism, intellectual disability, focal seizures, and multiple seizure types in the Gene-negative group. In conclusion, children with positive genetic findings exhibited more significant developmental delays/regression and poorer responses to treatment, underscoring the critical prognostic and therapeutic guidance value of genetic testing, while the treatment response observed at the 3-month mark serves as a significant predictor of long-term prognosis, offering a crucial reference for adjusting therapeutic strategies.
Noninvasive prenatal diagnosis relies on the analysis of the small amount of cell-free fetal DNA circulating in maternal plasma. Widely used to screen for chromosomal anomalies, the technique can also be applied to Mende...Noninvasive prenatal diagnosis relies on the analysis of the small amount of cell-free fetal DNA circulating in maternal plasma. Widely used to screen for chromosomal anomalies, the technique can also be applied to Mendelian diseases (NIPD-M). However, asserting the presence of a maternal variant in the fetus is challenging and requires the determination of the maternal haplotypes transmitted to the fetus. This is achieved via relative haplotype dosage (RHDO), a method that relies on the analysis of the allelic balance of multiple single-nucleotide polymorphisms around the pathogenic variant. An inherent risk of this method is that twin pregnancies and chromosomal anomalies like trisomy, monosomy or uniparental disomy unavoidably alter allelic balance, potentially leading to incorrect diagnosis. Here, we introduce an analytical method, fetal fraction signatures, that can detect such confounding situations in NIPD-M data, without the need for additional wet-lab work. We show that our method can reliably detect anomalies down to a low level of mosaicism and a low fetal fraction, thereby providing an essential quality-control tool for clinical testing by NIPD-M.
The RNA lariat debranching enzyme (DBR1) facilitates the hydrolysis of 2'-5' prime branched phosphodiester bonds. It acts on the bonds at the junction of excised lariat intron RNA, converting them into linear molecules f...The RNA lariat debranching enzyme (DBR1) facilitates the hydrolysis of 2'-5' prime branched phosphodiester bonds. It acts on the bonds at the junction of excised lariat intron RNA, converting them into linear molecules for degradation. Mutations in the gene result in the accumulation of lariat introns, leading to multiple system dysfunction. This case involves two siblings who exhibited a homozygous gene mutation in DBR1, identified as the variant c.200A>G p.(Tyr67Cys). Both showed similar manifestations, including premature birth, intrauterine growth restriction, growth deficiency, ichthyosis, encephalopathy, respiratory symptoms, and death within 12-13 months of life, some of which were reported in the literature. Additionally, they showed novel phenotypes, including laryngomalacia, hypotonia, elevated intracranial pressure, and hypospadias. It is important to state that these siblings had another sibling with a heterozygous form and who is healthy, which supports the pathogenicity of the homozygous state. Adding to the association between this mutation and encephalitis, our patients were found to be additionally susceptible to respiratory tract infections. Although many patients with central nervous system disorders ultimately develop pulmonary infections, this is frequently a consequence of progressive neurological impairment, including compromised airway clearance. This paper enriches the existing literature and emphasizes the pathogenicity of the homozygous form.
Nelson TJ, McGinn DE, Crowley TB
… +20 more, Rockart L, Green A, Giunta V, Tran O, Miller D, Breckpot J, Swillen A, Digilio MC, Unolt M, Putotto C, Pulvirenti F, Marino B, Emanuel BS, Zackai EH, Zhang ZD, Goldmuntz E, Boot E, Bassett AS, Morrow BE, McDonald-McGinn DM
This study is aimed at determining the spectrum of congenital heart disease associated with distal 22q11.22-23 deletions flanked by low copy repeats, LCR22 D-H. We analyzed cardiology findings in 128 unrelated individual...This study is aimed at determining the spectrum of congenital heart disease associated with distal 22q11.22-23 deletions flanked by low copy repeats, LCR22 D-H. We analyzed cardiology findings in 128 unrelated individuals with distal LCR22 D-H deletions. A total of 62 were newly described and 66 were derived from previous reports. We found that deletions which included LCR22-D as the proximal endpoint were the most prevalent in the cohort (104/128, 81.3%). Clinically relevant congenital heart disease was identified in 48 individuals (37.5%, 95% CI 29%-46%), which is lower than the prevalence reported for typical, proximal LCR22 A-D deletions (p = 3.7E-4), especially for conotruncal defects (13/128, 10.2%; p = 7.1E-13). Mild to moderate CHD predominated, including ventricular septal defects (22/128), bicuspid aortic valve (9/128) and mild cardiomyopathy (3/128). Persistent truncus arteriosus was the most prevalent (n = 8/13) conotruncal heart defect, but other anomalies also occurred in singleton cases. These findings support the need for cardiac evaluation in all individuals with distal 22q11.22-23 deletions, increased use of clinical genetic testing in syndromic individuals with these findings, and molecular studies in model systems. The results demonstrate that reduced gene dosage of distal 22q11.21-23, particularly within the D-E region including MAPK1 and HIC2 convey risk for CHD.
Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. We report a 27-year-old woman with right-sided colorectal...Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. We report a 27-year-old woman with right-sided colorectal cancer, café-au-lait macules, and an occipital neurofibroma. Tumor testing revealed microsatellite instability, loss of MLH1 and PMS2 expression, high tumor mutational burden (21.87 mutations/Mb), and wild-type BRAF. Germline analysis revealed a heterozygous MSH6 pathogenic variant inherited from her father. Additionally, MLH1 promoter hypermethylation was detected in peripheral blood DNA, consistent with constitutional mosaic epimutation. Constitutional epigenetic silencing of MLH1 is a rare but established cause of LS. This is the first reported case of a dual mechanism involving both a germline MSH6 variant and constitutional MLH1 methylation. The patient's unique clinical presentation and molecular profile challenged the conventional binary classification of MMR deficiency as either hereditary or sporadic, and highlight the complexity of MMR-related tumorigenesis. This case underscores the importance of comprehensive assessment integrating tumor and germline molecular data, particularly when clinical or molecular findings are atypical or discordant. The digenic etiology also raises questions regarding cancer surveillance and management strategies in such individuals.
Aubert Mucca M, Brunelle P, Doco Fenzy M
… +11 more, Vanlerberghe C, Dieux A, Feyereisen L, Jobic F, Lode L, Le Guyader G, Petit F, Schaefer E, Zaafrane-Khachnaoui K, Ziegler A, Patat O
Miller syndrome (MIM#263750) is a rare autosomal recessive acrofacial dysostosis associated with biallelic DHODH variants. Since the identification of the gene in 2010, five case reports have described a variable phenoty...Miller syndrome (MIM#263750) is a rare autosomal recessive acrofacial dysostosis associated with biallelic DHODH variants. Since the identification of the gene in 2010, five case reports have described a variable phenotype in only nine individuals from eight families. We present a cohort of 10 individuals from seven families affected by Miller syndrome, spanning the prenatal stage to 46 years of age. We report on the largest cohort of Miller syndrome to date, which highlights novel findings, including optic atrophy in multiple members of one consanguineous family. The typical postaxial limb defects, including the absence of the 5th digit, were consistent with prior descriptions, but we highlighted the frequent involvement of preaxial structures (thumb and tibial hypoplasia). A higher incidence of camptodactyly and the presence of facial nevus in two patients were notable findings. Congenital heart defects, primarily atrial septal defects, were common, and all living individuals had normal neurodevelopment. This cohort expands the phenotypic spectrum of Miller syndrome associated with variation in DHODH, presenting new findings such as preaxial involvement and facial nevus simplex. Optic atrophy in one family could prompt screening of other cases. Early prenatal diagnosis, particularly in the presence of cardinal limb and cardiac malformations, is crucial for management and genetic counseling.
This case highlights the complexity of diagnosing dual rare metabolic diseases and the importance of genetic testing in uncovering novel pathogenic variants. It has also contributed to expanding the clinical manifestatio...This case highlights the complexity of diagnosing dual rare metabolic diseases and the importance of genetic testing in uncovering novel pathogenic variants. It has also contributed to expanding the clinical manifestation spectrum of B4GALT1-CDG, which is an ultra-rare disorder.
A patient of intellectual developmental disorder with autism and macrocephaly (IDDAM) caused by a novel CHD8 mutation developed adult-onset compulsive behaviors in addition to the core phenotype in early life. This case...A patient of intellectual developmental disorder with autism and macrocephaly (IDDAM) caused by a novel CHD8 mutation developed adult-onset compulsive behaviors in addition to the core phenotype in early life. This case expands the clinical and genotypic spectrums of IDDAM which may inspire future studies on genotype-phenotype correlation and the disease course.
FAM20B encodes glycosaminoglycan xylosylkinase, a key enzyme in proteoglycan biosynthesis. Biallelic pathogenic variants have only recently been linked to skeletal dysplasia. We report two pregnancies from one couple, re...FAM20B encodes glycosaminoglycan xylosylkinase, a key enzyme in proteoglycan biosynthesis. Biallelic pathogenic variants have only recently been linked to skeletal dysplasia. We report two pregnancies from one couple, resulting in three fetuses (twin sibs and younger sib) with severe skeletal anomalies. Prenatal findings included enlarged nuchal translucency, short bowed and dislocated limbs, intrauterine growth restriction, and multiple malformations. Intra-uterine fetal death occurred in Probands 1 and 2, and neonatal death of Proband 3. Postnatally, all three probands showed limb shortening with joint (sub)luxations and contractures, and craniofacial dysmorphisms. SNP-array and exome analysis revealed compound heterozygosity for two novel FAM20B variants: a paternal ~8 kb deletion encompassing the terminal exon and a maternal missense variant (p.Arg290Cys) at an evolutionary conserved position. The same amino acid residue was previously affected in a child with a milder phenotype. In silico modeling supports a destabilizing effect of the missense change on protein structure, especially due to the loss of a salt bridge essential for catalytic function. This report describes the prenatal phenotype of FAM20B-related dysplasia and can help establish the phenotypic spectrum of the disorder. It further supports the essential role of FAM20B in early skeletal development.
Pathogenic germline variants in DICER1 predispose to pleuropulmonary blastoma, multinodular goitre, embryonal rhabdomyosarcomas of the uterine cervix, ovarian Sertoli-Leydig cell tumour and a broader spectrum of patholog...Pathogenic germline variants in DICER1 predispose to pleuropulmonary blastoma, multinodular goitre, embryonal rhabdomyosarcomas of the uterine cervix, ovarian Sertoli-Leydig cell tumour and a broader spectrum of pathologies. Here, we report a 35-year-old female with diagnoses of pineoblastoma, embryonal rhabdomyosarcoma, leiomyosarcoma, two meningiomas, and a germline DICER1 c.4206+1G>C, p.(?) variant. The variant was classified as a variant of unknown significance (VUS) based on the current ACMG/AMP gene-specific DICER1 guidelines. Additional functional analysis showed that the variant clearly abrogates the function of DICER1 and therefore PS3_Supporting evidence is included in the classification. Based on this the variant is reclassified as likely pathogenic. Moreover, our data suggest that the current ACMG/AMP gene-specific DICER1 guidelines should be modified in relation to the level of evidence strength (moderate to strong/very strong) for exon 22 skipping as well as to the use of the functional evidence (PS3) code.
Koutsis G, Chelban V, Kartanou C
… +17 more, Kontogeorgiou Z, Koniari C, Ragazos N, Voudommatis C, Zhelcheska K, Lynch DS, Maroofian R, Barkhordari E, Mohammad R, Zaganas I, Drakos M, Xiromerisiou G, Dardiotis E, Stefanis L, Panas M, Houlden H, Karadima G
Hereditary spastic paraplegia (HSP) is a neurogenetic disorder characterized by progressive, length-dependent degeneration of the upper motor neurons. We investigated 112 Greek HSP index cases collected over more than 25...Hereditary spastic paraplegia (HSP) is a neurogenetic disorder characterized by progressive, length-dependent degeneration of the upper motor neurons. We investigated 112 Greek HSP index cases collected over more than 25 years from all regions of the country, using a combination of next generation sequencing and multiplex ligation-dependent probe amplification. In total, we identified a causative variant in 68 patients, corresponding to a diagnostic yield of 60.7%. The diagnostic yield was 62.8% in autosomal dominant HSP, 77.8% in autosomal recessive HSP and 50.0% in sporadic cases. We identified 7 novel causative variants in SPAST, SPG7, and CYP7B1. We found causative variants in a total of 18 different genes. The most commonly involved genes, affecting more than one family, were SPAST (25.0%), SPG11 (12.5%), CYP7B1 (3.6%), SPG7 (3.6%), KIF5A (2.7%), ABCD1 (1.8%) and PSEN1 (1.8%). Variants in ATL1, REEP1, BSCL2, PLP1, WASCHC5, AP5Z1, CYP27A1, SOD1, POLR3A, GFAP and ARG1 were identified in single families. This study presents a comprehensive overview of the phenotypic and genotypic spectrum of HSP in the Greek population, expanding previous data, and contributing to the characterisation of further pathogenic variants linked to HSP.
To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the whole-exome sequencin...To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the whole-exome sequencing data from 280 CHH probands, we identified 15 potential splice-site variants in CHD7, ANOS1 and FGFR1 by using in silico software. The functional consequences of these variants were analyzed by the minigene assay or RT-PCR analyses of RNA taken from the peripheral lymphocytes. Detailed phenotyping was performed in the CHH patients harboring deleterious variants and their available family members. 11 out of 15 potential splice-site variants were demonstrated to cause mis-splicing, resulting in loss of function through deletion, insertion or frameshift of amino acids in the proteins. Most patients with deleterious splice-site variants in CHD7, ANOS1, FGFR1 presented with gene-specific non-reproductive phenotypes, confirming the pathogenic contribution of these variants to CHH. Our study indicated that splice-site variants in CHD7, ANOS1, FGFR1 underlie the genetic basis of ~3.9% of CHH patients, warranting the inclusion of potential splice-site variants for genetic diagnosis and counseling of CHH.
Primary ciliary dyskinesia (PCD) is a genetic disease caused by variants affecting more than 50 cilia genes. We report the prevalence and distribution of all known and novel variants in children with PCD in Qatar. The co...Primary ciliary dyskinesia (PCD) is a genetic disease caused by variants affecting more than 50 cilia genes. We report the prevalence and distribution of all known and novel variants in children with PCD in Qatar. The cohort included 28 children: 16 Qatari, 3 Egyptian, 2 Tunisian, 1 Sudanese, 1 Algerian, 1 Pakistani, 2 Iranian, and 2 Indian. Consanguinity rate was 82.1%. Median age at diagnosis was 7.5 years (IQR: 0.6-11.8). Situs inversus was present in 7 (25%) patients, chronic cough in 25 (89.3%), chronic sinusitis in 17 (60.7%), and bronchiectasis in 16 (61%). Median FEV1 was 71% (IQR: 58%-82%), FVC was 80% (IQR: 74%-91%), and FEV1/FVC ratio was 79% (IQR: 68%-84%). The most frequent variant in native Qataris was c.5924+1G>C in DNAH11 (seven patients). Eight novel variants were found in the cohort: c.6565C>T in DNAH11 (two patients); c.368-369del in DNAAF3 (one patient); c.357G>A in DNAFF2 (one patient); c.278G>A in DNAAF2 (one patient); c.1666-9C>G (intronic) in CCDC39 (two patients); c.9105+2T>C (splice donor) in DNAH5 (two patients); c.8647+3A>G (intronic) in DNAH5 (two patients); c.916G>T in ODAD4 gene (two patients). Wide genetic variation was found among PCD children in Qatar, including several novel variants, reflecting their ethnic diversity. Genetic variation was less among native Qatari patients due to high consanguinity.
Dominant mutations in the calcium permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically result in skeletal dysplasia or peripheral neuromuscular disease. However, the full spectrum of TRPV4-rel...Dominant mutations in the calcium permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically result in skeletal dysplasia or peripheral neuromuscular disease. However, the full spectrum of TRPV4-related phenotypes remains incompletely defined. This study systematically reviewed the clinical and genetic features of 10 Chinese patients harboring various TRPV4 variants. In the cohort, six patients were diagnosed with spondylometaphyseal dysplasia Kozlowski type (SMDK) and four patients with metatropic dysplasia (MD). The most common features involved spinal deformity (platyspondyly, kyphosis or scoliosis), and lower-limb malalignments (genu varum, genu valgum, or leg-length discrepancy). Two patients with MD had neurological deficits. The R594H and P799R substitutions were the most recurrent variants in our study. A novel variant (c.1628T>G, p.L543R) in the S2-S3 loop was identified. The study seeks to improve diagnostic precision by combining genetic and radiographic assessment, and highlights the importance of early spinal surveillance and multidisciplinary care to prevent neurological complications underlying TRPV4-mediated disorders.
Hirschsprung disease (HD) can be associated with congenital central hypoventilation syndrome (CCHS). CCHS is mostly due to PHOX2B pathogenic variants. First report of HD on fetal autopsy leading to CCHS diagnosis. Highli...Hirschsprung disease (HD) can be associated with congenital central hypoventilation syndrome (CCHS). CCHS is mostly due to PHOX2B pathogenic variants. First report of HD on fetal autopsy leading to CCHS diagnosis. Highlights the role of fetal autopsy in stillborn babies, to guide genetic investigation and refine genetic counseling.
Hereditary spastic paraplegia type 62 (SPG62) is a neurodegenerative disorder, with more than 20 individuals reported to date. This ultra-rare entity is inherited in an autosomal recessive manner and has been associated...Hereditary spastic paraplegia type 62 (SPG62) is a neurodegenerative disorder, with more than 20 individuals reported to date. This ultra-rare entity is inherited in an autosomal recessive manner and has been associated with ERLIN1 variants. In addition, ERLIN1-related biallelic variants have been linked to early-onset amyotrophic lateral sclerosis (ALS). We present two siblings with slowly progressive spastic paraplegia, with mild intellectual decline, behavioral findings, and hyperacusis. This study expands the clinical spectrum of hereditary spastic paraplegia associated with ERLIN1.
Williams KM, Berger W, Koller S
… +12 more, Pfiffner FK, Maspoli A, Gloggnitzer J, Brühwiler BVT, Stathopoulos C, Munier F, Allen L, Iosifidis C, Black GC, Sergouniotis PI, Lloyd IC, Gerth-Kahlert C
Pathogenic variants in ADAMTSL4 are an important cause of isolated ectopia lentis with an increasing number of genetically confirmed cases internationally. We sought to better describe ocular features seen with pathogeni...Pathogenic variants in ADAMTSL4 are an important cause of isolated ectopia lentis with an increasing number of genetically confirmed cases internationally. We sought to better describe ocular features seen with pathogenic variants in ADAMTSL4. We performed a retrospective, multicenter study examining the phenotypic and genotypic spectrum of ADAMTSL4-associated ocular disease. We identified 41 individuals from 32 families with genetically confirmed ADAMTSL4-related disease across six tertiary referral centers across Europe. Identified participants had a young age of diagnosis (median 1.3 years) and a highly myopic refractive error (mean SE -10.27 D). A diagnosis of ectopia lentis et pupillae was made in a third of cases, with a younger age at diagnosis (median 0.5 years). Subluxation tended to be in the inferior direction (~33%). Zonules were noted to be missing or absent in the majority of cases. Sixteen different pathogenic variants in ADAMTSL4 were reported. A previously reported 20-bp deletion (c.767_786del) was highly prevalent in this cohort (23/32), and all ectopia lentis et pupillae cases carried this variant. ADAMTSL4-related disease tends to present at a younger age and be associated with higher myopia than other forms of ectopia lentis (such as FBN1). Early identification of typical phenotypic features alongside genetic testing can aid early, precise diagnosis and prevent unnecessary investigations.