Expanding the phenotype of the recurrent truncating eIF2γ pathogenic variant p.(Ile465Serfs*4) identified in two brothers with MEHMO syndrome.
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ABSTRACT:
SUBMITTER: Ygberg S
PROVIDER: S-EPMC9207232 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rare pathogenic EIF2S3 missense and terminal deletion variants cause the X-linked intellectual disability (ID) syndrome MEHMO, or a milder phenotype including pancreatic dysfunction and hypopituitarism. We present two unrelated male patients who carry novel EIF2S3 pathogenic missense variants (p.(Thr144Ile) and p.(Ile159Leu)) thereby broadening the limited genetic spectrum and underscoring clinically variable expressivity of MEHMO. While the affected male with p.(Thr144Ile) presented with severe motor delay, severe microcephaly, moderate ID, epileptic seizures responsive to treatments, hypogenitalism, central obesity, facial features, and diabetes, the affected male with p.(Ile159Leu) presented with moderate ID, mild motor delay, microcephaly, epileptic seizures resistant to treatment, central obesity, and mild facial features. Both variants are located in the highly conserved guanine nucleotide binding domain of the EIF2S3 encoded eIF2γ subunit of the heterotrimeric translation initiation factor 2 (eIF2) complex. Further, we investigated both variants in a structural model and in yeast. The reduced growth rates and lowered fidelity of translation with increased initiation at non-AUG codons observed for both mutants in these studies strongly support pathogenicity of the variants.
| S-EPMC7584729 | biostudies-literature
Project description:BackgroundPURA syndrome is rare autosomal dominant condition characterized by moderate to severe neurodevelopmental delay with absence of speech in nearly all patients and lack of independent ambulation in many. Early-onset problems include excessive hiccups, hypotonia, hypersomnolence, hypothermia, feeding difficulties, recurrent apneas, epileptic seizures, and abnormal nonepileptic movements. Other less common manifestations comprise congenital heart defects, urogenital malformations, and various skeletal, ophthalmological, gastrointestinal, and endocrine anomalies. Up to now, 78 individuals with PURA syndrome and 64 different pathogenic variants have been reported, but no clear-cut genotype-phenotype correlations have emerged so far. Herein, we report the clinical and molecular characterization of a 3-year-old girl with severe hypotonia, global developmental delay, and soft, loose skin, who came to our attention with a suspicion of cutis laxa (CL), which denotes another condition with variable neurodevelopmental problems.MethodsAmplicon-based whole exome sequencing was performed, and an in-house pipeline was used to conduct filtering and prioritization of variants. New prediction algorithms for indels were used to validate the pathogenicity of the PURA variant, and results were confirmed with the Sanger method. Finally, we collected clinical and mutational data of all PURA syndrome patients reported yet and compared the clinical features with those of our patient.ResultsClinical evaluation and biochemical investigations excluded CL and prompted to perform whole exome sequencing, which confirmed the absence of pathogenic variants in all CL-related genes and revealed the known PURA c.697_699del, p.(Phe233del) variant, identified hitherto in seven additional children with PURA syndrome.ConclusionsOur data expand the phenotypic spectrum of PURA syndrome by showing that it can be regarded as a differential diagnosis for cutis laxa in early infancy. Our patient and literature review emphasize that a wide clinical variability exists not only between individuals with different PURA variants, but also among patients with the same causal mutation.
| S-EPMC7963414 | biostudies-literature
Project description:Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C.
| S-EPMC3895633 | biostudies-literature
Project description:BackgroundCraniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant.MethodsWhole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis.ResultsOn whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans.ConclusionsThis finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant.
| S-EPMC6565579 | biostudies-literature
Project description:Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.316 G > A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.
| S-EPMC6169784 | biostudies-literature
Project description:BackgroundShashi-Pena syndrome (SHAPNS) is a developmental disorder caused by mutations in additional sex combs-like Protein 2 (ASXL2). Since 2016, only 12 cases from 10 families have been reported. However, neonatal period characteristics remain largely unknown. Herein, we report a case with a pathogenic variant in ASXL2 in a newborn.Case descriptionA newborn was diagnosed with a previously unreported de novo truncating mutation in ASXL2 (NM_018263.6) at 21 days and the clinical characteristics of all probands with ASXL2-related SHAPNS was reported in the literature. He had persistent hypoglycemia caused by inappropriate insulin levels and achieved stable glucose levels after octreotide treatment. Magnetic resonance imaging (MRI) revealed a small cerebellum, and fundoscopy showed bilateral retinal paving-stone-like white lesions. The results of trio-based whole exome sequencing (WES) were returned on the 21st day of life, and a heterozygous de novo truncating pathogenic c.1792C>T (p.Gln598*) variant in exon 11 of the ASXL2 gene was identified. The clinical features of our patient and another 10 probands with ASXL2-related SHAPNS reported in the literature were included in this review. More than half shared recognizable clinical features, including hypertelorism (11/11), broad nasal tip (10/11), arched eyebrows (9/11), a large V-shaped glabellar nevus flammeus on the forehead (9/11), low-set ears (8/11), posteriorly rotated ears (7/11), proptosis (6/11) and deep palm creases (6/11). Major clinical issues included feeding difficulties (10/11), developmental delay (10/11), skeletal and/or extremity abnormalities (8/11), progressive macrocephaly (8/11), hypotonia (8/11), hypoglycemia (6/11) and seizures (6/11). Neurodevelopmental regression was possible in patients (2/11) with normal MRI findings who later developed nonfebrile seizures.ConclusionsWe present a newborn diagnosing the SHAPNS by trio-WES, which is the earliest age of diagnosis. The application of octreotide for hypoglycemia, the small cerebellum and bilateral paving-stone-like white lesions of the retinas are described for the first time in an individual with ASXL2-related SHAPNS. Additional clinical reports of neonates with damaging ASXL2 variants are necessary to verify the mechanism and optimal treatment of ASXL2-related hypoglycemia, neurological damage and optic impairment. Neurological, endocrinological, ophthalmological, and rehabilitative follow-ups of these patients are necessary and important.
| S-EPMC9926125 | biostudies-literature
Project description:PURPOSE:TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. METHODS:We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. RESULTS:The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. CONCLUSION:TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.
| S-EPMC6752277 | biostudies-literature
Project description:BackgroundWolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome caused by partial 4p deletion highly variable in size in individual patients. The core WHS phenotype is defined by the association of growth delay, typical facial characteristics, intellectual disability and seizures. The WHS critical region (WHSCR) has been narrowed down and NSD2 falls within this 200 kb region. Only four patients with NSD2 variants have been documented with phenotypic features in detail.Case presentationHerein, we report the case of a 12-year-old boy with developmental delay. He had dysmorphic facial features including wide-spaced eyes, prominent nasal bridge continuing to forehead, abnormal teething and micrognathia. He also had mild clinodactyly of both hands. Using whole-exome sequencing, we identified a pathogenic mutation in NSD2 [c.4029_4030insAA, p.Glu1344Lysfs*49] isolated from peripheral blood DNA. Sanger confirmation of this variant revealed it as a de novo truncating variant in the family.ConclusionHere, we reported a boy with de novo truncating variant in NSD2 with atypical clinical features comparing with 4p16.3 deletion related WHS. Our finding further supported the pathogenesis of truncating variants in NSD2 and delineated the possible symptom spectrum caused by these variants.
| S-EPMC6683463 | biostudies-literature
Project description:RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias with microcephalic osteodysplastic primordial dwarfism, type 1 having a more severe phenotype than Roifman syndrome. Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. The features also overlap with Lowry Wood syndrome, another rare but well-defined skeletal dysplasia for which the genetic etiology has not been identified. Characteristic features include multiple epiphyseal dysplasia and microcephaly. Here, we describe three patients with Lowry Wood syndrome with biallelic RNU4ATAC pathogenic variants. This report expands the phenotypic spectrum for biallelic RNU4ATAC disorder causing variants and is the first to establish the genetic cause for Lowry Wood syndrome.
| S-EPMC6774248 | biostudies-literature
Project description:Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val) in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. PIGT encodes a crucial subunit of the glycosylphosphatidylinositol (GPI) transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel PIGT variant.
| S-EPMC5192484 | biostudies-literature