scholarly journals A novel frameshift pathogenic variant in ST3GAL5 causing salt and pepper developmental regression syndrome (SPDRS): A case report

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Jamal Manoochehri ◽  
Seyed Alireza Dastgheib ◽  
Hossein Jafari Khamirani ◽  
Maryam Mollaie ◽  
Zahra Sharifi ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Cerebral Atrophy ◽  
Failure To Thrive ◽  
Pathogenic Variant ◽  
Iranian Patient ◽  
Developmental Regression ◽  
Gm3 Synthase ◽  
Phenotypic Spectrum ◽  
Salt And Pepper ◽  
Atonic Seizures

AbstractGM3 synthase deficiency is associated with salt and pepper developmental regression syndrome (SPDRS), a rare genetic disorder. Herein, we report the first Iranian patient with SPDRS. We detected a novel pathogenic variant of ST3GAL5 (NM_003896.4: c.1030_1031del, p.Ile344Cysfs*11). The proband had intellectual disability (ID), failure to thrive, cerebral atrophy, microcephaly, and atonic seizures. The main future challenge proceeding from the results of this study is the prenatal detection of the newly discovered variant; the next step would involve further studies to elucidate the phenotypic spectrum of SPDRS and detect new variants that could cause symptoms ranging from mild to severe.

scholarly journals Correction: A novel frameshift pathogenic variant in ST3GAL5 causing salt and pepper developmental regression syndrome (SPDRS): a case report

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Jamal Manoochehri ◽  
Seyed Alireza Dastgheib ◽  
Hossein Jafari Khamirani ◽  
Maryam Mollaie ◽  
Zahra Sharifi ◽  
...  
Keyword(s):  
Case Report ◽  
Pathogenic Variant ◽  
Developmental Regression ◽  
Salt And Pepper

scholarly journals First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant?

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Mario Tumminello ◽  
Antonella Gangemi ◽  
Federico Matina ◽  
Melania Guardino ◽  
Bianca Lea Giuffrè ◽  
...  
Keyword(s):  
Ectodermal Dysplasia ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Hypohidrotic Ectodermal Dysplasia ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Clinical Potential ◽  
Genomic Variant ◽  
Eda Gene

Abstract Background Hypohidrotic Ectodermal Dysplasia (HED) is a genetic disorder which affects structures of ectodermal origin. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of disease. XLHED is characterized by hypotrichosis, hypohydrosis and hypodontia. The cardinal features of classic HED become obvious during childhood. Identification of a hemizygous EDA pathogenic variant in an affected male confirms the diagnosis. Case presentation We report on a male newborn with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. Gene panel sequencing identified a new hemizygous missense variant of uncertain significance (VUS) c.1142G > C (p.Gly381Ala) in the EDA gene, located on the X chromosome and inherited from the healthy mother. Conclusion Despite the potential functional impact of VUS remains uncharacterized, our goal is to evaluate the clinical potential consequences of missense VUS on EDA gene. Even if the proband’s phenotype is characteristic for classic HED, further reports of patients with same clinical phenotype and the same genomic variant are needed to consider this novel VUS as responsible for the development of HED.

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

scholarly journals Boricua Founder Variant in FRRS1L Causes Epileptic Encephalopathy With Hyperkinetic Movements

2020 ◽  
Vol 36 (2) ◽  
pp. 93-98
Author(s):  
Imane Abdelmoumen ◽  
Sandra Jimenez ◽  
Ignacio Valencia ◽  
Joseph Melvin ◽  
Agustin Legido ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Puerto Rican ◽  
Cerebellar Atrophy ◽  
Intractable Epilepsy ◽  
Brain Magnetic Resonance Imaging ◽  
Epileptic Encephalopathy ◽  
Pathogenic Variant ◽  
Global Developmental Delay ◽  
Neurodevelopmental Outcomes ◽  
Developmental Regression

Objective: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. Background: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. Methods: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. Results: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). Conclusions: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.

scholarly journals Neonatal Bartter syndrome: A case report from Northern India

2021 ◽  
pp. 10-14
Author(s):  
Astitva Singh ◽  
Nishant Sharma ◽  
Prachi Agarwal ◽  
Bolledu Swaroop Anand ◽  
Akshay Shukla
Keyword(s):  
Case Report ◽  
Genetic Disorder ◽  
Failure To Thrive ◽  
Bartter Syndrome ◽  
Thick Ascending Limb ◽  
Older Children ◽  
Northern India ◽  
Tubular System ◽  
Renal Tubular ◽  
Neonatal Bartter Syndrome

Abstract. Bartter Syndrome is a rare genetic disorder affecting the renal tubular system causing a decreased absorption of sodium and chloride in the thick ascending limb of the Henle loop. Most children present in infancy with complaints of polyuria, polydipsia, vomiting, constipation and failure to thrive while older children present with recurrent episodes of dehydration, muscle weakness and cramps. The present study aimed to demonstrate a case of Bartter syndrome presenting as acute gastroenteritis.

A Novel Mutation in Aicardi–Goutières' Syndrome: A Case Report

2020 ◽  
Author(s):  
Motahareh Sheikh-Hosseini ◽  
Mohammad Moarefzadeh ◽  
Hamideh Alavi-Moghaddam ◽  
Saeid Morovvati
Keyword(s):  
Neonatal Jaundice ◽  
Clinical Phenotype ◽  
Novel Mutation ◽  
Genetic Disorder ◽  
Cerebral Atrophy ◽  
Pathogenic Mutation ◽  
Consanguineous Marriage ◽  
The Other ◽  
Congenital Infections ◽  
History Of

AbstractAicardi–Goutières' syndrome (AGS) is a rare heterogeneous genetic disorder characterized by encephalopathy and may bear resemblance to congenital infections. The prevalence of AGS is estimated at more than 4,000 worldwide. Mutations in TREX1 gene are present in ∼22% of patients. We present the case of a 2-year-old boy who came to the Biogene laboratory (Tehran, Iran) with a constellation of congenital disorders but no clear diagnosis. His clinical phenotype consisted of neonatal jaundice, relative microcephaly with diffuse cerebral atrophy in both hemispheres, developmental delay, hypotonia, and nystagmus. There was history of parental consanguineous marriage and prematurity. In our study, a homozygous potentially pathogenic mutation in TREX1 gene associated with AGS1 was detected. This mutation has not been reported in the other patients with AGS. A novel frameshift homozygous potentially pathogenic mutation in TREX1 is postulated to be the cause of disease in our patient.

Blended Phenotype of Pelger-Huet Anomaly with Osteochondroma and Autosomal Recessive Deafness with Enlarged Vestibular Aqueduct

2022 ◽  
pp. 1-6
Author(s):  
Tayfun Cinleti ◽  
Ceren Yılmaz Uzman ◽  
Şefika Akyol ◽  
Özlem Tüfekçi ◽  
Murat Derya Erçal ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Pathogenic Variant ◽  
Nuclear Chromatin ◽  
Pendred Syndrome ◽  
Enlarged Vestibular Aqueduct ◽  
Skeletal Abnormalities ◽  
Vestibular Aqueduct ◽  
Phenotypic Spectrum ◽  
Molecular Studies ◽  
Patient Will

Pelger-Huet anomaly (PHA) is a benign hematological anomaly that is characterized by impaired lobulation of neutrophils with a coarse nuclear chromatin. Skeletal abnormalities may accompany this anomaly. Autosomal recessive deafness-4 (DFNB4) with enlarged vestibular aqueduct (EVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL). We report a case with SNHL, multiple skeletal anomalies including osteochondroma, developmental delay, and PHA. Molecular studies revealed a heterozygous pathogenic variant in the <i>LBR</i> gene and a homozygous likely pathogenic variant in the <i>SLC26A4</i> gene. Due to these 2 variants, he was diagnosed with PHA and DFNB4 with EVA. If goiter develops, DFNB4 with EVA is named Pendred syndrome (PDS), so the patient will be followed up for this condition, and in the current literature, there is no case with PDS and PHA co-existence either. PHA may be accompanied by multiple skeletal abnormalities. In our case, there is also concomitance with osteochondroma. Although these are independent and distinct diagnoses, we present this case due to the concomitance of these situations.

A Novel Frameshift Mutation in Abnormal Spindle-Like Microcephaly (ASPM) Gene in an Iranian Patient with Primary Microcephaly: A Case Report

2020 ◽  
Author(s):  
Afsaneh BAZGIR ◽  
Mehdi AGHA GHOLIZADEH ◽  
Faezeh SARVAR ◽  
Zahra PAKZAD
Keyword(s):  
Intellectual Disability ◽  
Frameshift Mutation ◽  
Genetic Disorder ◽  
Normal Function ◽  
Molecular Testing ◽  
Homozygous Mutation ◽  
Primary Microcephaly ◽  
Iranian Patient ◽  
Whole Exome ◽  
Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder, leading to the defect of neurogenic brain development. Individuals with MCPH reveal reduced head circumference and intellectual disability. Several MCPH loci have been identified from several populations. Genetic heterogeneity of this disorder represents molecular testing challenge. An 8 yr old female, born from consanguineous parents, was attended to Fardis Central Lab, Alborz, Iran. Based on the reduced circumference and intellectual disability, MCPH was diagnosed. Whole exome sequencing of the patient identified a novel homozygous frameshift mutation (c.2738dupT, p.Cys914fs) in exon 9 Abnormal Spindle-like Microcephaly )ASPM( gene. By Sanger sequencing, segregation analysis showed that both parents were heterozygous carriers for this variant. The novel frameshift mutation likely truncates the protein, resulting in loss of normal function ASPM in homozygous mutation carriers. The study might add a new pathogenic variant in mutations of the ASPM gene as a causative variant in patients with MCPH and might be helpful in genetic counseling of consanguineous families.

scholarly journals ST3GAL5-Related Disorders: A Deficiency in Ganglioside Metabolism and a Genetic Cause of Intellectual Disability and Choreoathetosis

2018 ◽  
Vol 33 (13) ◽  
pp. 825-831 ◽  
Author(s):  
Eliza Gordon-Lipkin ◽  
Julie S. Cohen ◽  
Siddharth Srivastava ◽  
Bruno P. Soares ◽  
Eric Levey ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorder ◽  
Failure To Thrive ◽  
Ganglioside Gm3 ◽  
Normal Birth ◽  
Pathogenic Variants ◽  
Gm3 Synthase ◽  
Whole Exome ◽  
Ganglioside Metabolism ◽  
Autosomal Recessive Condition

GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.

scholarly journals Implementation of second-tier tests in newborn screening for the detection of vitamin B12 related acquired and genetic disorders: results on 258,637 newborns

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Sonia Pajares ◽  
Jose Antonio Arranz ◽  
Aida Ormazabal ◽  
Mireia Del Toro ◽  
Ángeles García-Cazorla ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Clinical Symptoms ◽  
Screening Program ◽  
Genetic Disorders ◽  
Failure To Thrive ◽  
Propionic Acidemia ◽  
Screening Strategy ◽  
Vitamin B ◽  
Developmental Regression ◽  
Second Tier

Abstract Background Alteration of vitamin B12 metabolism can be genetic or acquired, and can result in anemia, failure to thrive, developmental regression and even irreversible neurologic damage. Therefore, early diagnosis and intervention is critical. Most of the neonatal cases with acquired vitamin B12 deficiency have been detected by clinical symptoms and only few of them trough NBS programs. We aim to assess the usefulness of the second-tier test: methylmalonic acid (MMA), methylcitric acid (MCA) and homocysteine (Hcys) in our newborn screening program and explore the implications on the detection of cobalamin (vitamin B12) related disorders, both genetic and acquired conditions. Methods A screening strategy using the usual primary markers followed by the analysis of MMA, MCA and Hcys as second tier-test in the first dried blood spot (DBS) was developed and evaluated. Results During the period 2015–2018 a total of 258,637 newborns were screened resulting in 130 newborns with acquired vitamin B12 deficiency (incidence 1:1989), 19 with genetic disorders (incidence 1:13,613) and 13 were false positive. No false negatives were notified. Concerning the second-tier test, the percentage of cases with MMA above the cut-off levels, both for genetic and acquired conditions was very similar (58% and 60%, respectively). Interestingly, the percentage of cases with increased levels of Hcys was higher in acquired conditions than in genetic disorders (87% and 47%, respectively). In contrast, MCA was high only in 5% of the acquired conditions versus in 53% of the genetic disorders, and it was always very high in all patients with propionic acidemia. Conclusions When screening for methylmalonic acidemia and homocystinuria, differential diagnosis with acquired vitamin B12 deficiency should be done. The results of our strategy support the inclusion of this acquired condition in the NBS programs, as it is easily detectable and allows the adoption of corrective measures to avoid the consequences of its deficiency.

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