scholarly journals New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform

2021 ◽  
Vol 22 (5) ◽  
pp. 2262
Author(s):  
Víctor Abad-Morales ◽  
Ana Wert ◽  
María Ángeles Ruiz Gómez ◽  
Rafael Navarro ◽  
Esther Pomares
Keyword(s):  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Severe Form ◽  
Compound Heterozygous ◽  
Healthy Human ◽  
Systemic Involvement ◽  
Pathogenic Variants ◽  
Nicotinamide Mononucleotide ◽  
Transcriptional Alterations ◽  
Epiphyseal Dysplasia

This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.

scholarly journals Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: late diagnosis and gender reassignment in a two-year-old child

2021 ◽  
Vol 67 (5) ◽  
pp. 53-57
Author(s):  
N. Yu. Raygorodskaya ◽  
E. P. Novikova ◽  
A. N. Tyulpakov ◽  
M. A. Kareva ◽  
N. A. Nikolaeva ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Clinical Case ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Gender Reassignment ◽  
And Gender ◽  
21 Hydroxylase Deficiency

11β-hydroxylase deficiency is a rare autosomal recessive disorder due to impaired steroidogenesis in the adrenal cortex caused by pathogenic mutations in the CYP11B1 gene. The main clinical manifestations are determined by a deficiency of cortisol, ACTH hyperproduction, excessive androgens secretion and the accumulation of 11-deoxycorticosterone, which leads to the development of arterial hypertension. In the diagnostic search, it is important to take into account the ethnicity of the patient, since the frequency of the disease and the prevalence of mutations differ between ethnic groups. The article presents a clinical case of 11β-hydroxylase deficiency as the result of compound heterozygous mutations in the CYP11B1 gene in a patient of Turkic origin. This case shows the clinical manifestations and the development of complications of 11β-hydroxylase deficiency, the stages of differential diagnosis of patients with 21-hydroxylase deficiency.

scholarly journals Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aliaa H. Abdelhakim ◽  
Avinash V. Dharmadhikari ◽  
Sara D. Ragi ◽  
Jose Ronaldo Lima de Carvalho ◽  
Christine L. Xu ◽  
...  
Keyword(s):  
Coenzyme Q ◽  
Clinical Manifestations ◽  
Missense Variant ◽  
Neurological Involvement ◽  
Cone Dystrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
End Stage

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

A clinical case of severe Duchenne muscular dystrophy caused by a nonsense mutation in the DMD gene in a girl

2021 ◽  
Vol 2 (4) ◽  
pp. 227-232
Author(s):  
Tatyana V. Podkletnova ◽  
Olga B. Kondakova ◽  
Eugeniya V. Uvakina ◽  
Dariya A. Fisenko ◽  
Anastasiya A. Lyalina ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
X Chromosome ◽  
Clinical Symptoms ◽  
Chromosomal Rearrangements ◽  
Clinical Manifestations ◽  
Severe Form ◽  
Rapid Progression ◽  
Compound Heterozygous ◽  
Dmd Gene

Duchenne muscular dystrophy (DMD) is a hereditary progressive muscular dystrophy, mainly manifested in boys, is characterized by the onset at an early age, gradual symmetrical atrophy of the striated musculature of the limbs, trunk, as well as damage to the heart muscle. As a rule, girls and women inheriting a pathological mutation are classified only as its carriers and do not have clinical manifestations of the disease. Rare cases when women or girls show clinical manifestations of DMD may be due to chromosomal rearrangements involving the region of the short arm of the X chromosome (Xp21.2), deletions of this region, complete loss of the X chromosome (Shereshevsky-Turner syndrome), homogenous X chromosome dysomnia, compound heterozygous state for two pathogenic mutations in the DMD gene, nonequilibrium inactivation of the X chromosome. When female mutation carriers have DMD clinical symptoms, they usually manifest much milder than boys and young males. Descriptions of patients with the severe course and rapid progression of the disease, comparable in the rate of progression with boys, are rare. In this article, the authors share their experience of observing a girl patient who suffered from a severe form of DMD.

scholarly journals The genetic basis of classical galactosaemia in Polish patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Aleksandra Jezela-Stanek ◽  
Anna Bauer ◽  
Katarzyna Wertheim-Tysarowska ◽  
Jerzy Bal ◽  
Agnieszka Magdalena Rygiel ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Genetic Basis ◽  
Dna Analysis ◽  
Current Knowledge ◽  
Autosomal Recessive Disorder ◽  
Molecular Characteristics ◽  
Compound Heterozygous ◽  
Classic Galactosemia ◽  
Pathogenic Variants ◽  
Molecular Etiology

AbstractClassic galactosemia (OMIM #230400) is an autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the galactose-1-phosphate uridylyltransferase gene (GALT; 606999) on chromosome 9p13. Its diagnosis is established by detecting elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity. Biallelic pathogenic variants in the GALT gene is confirmed by DNA analysis. Our paper presents molecular characteristics of 195 Polish patients diagnosed with galactosemia I, intending to expand the current knowledge of this rare disease's molecular etiology. To the best of our knowledge, the described cohort of galactosemia patients is the largest single-center cohort presented so far.

scholarly journals Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease

2020 ◽  
Vol 10 (11) ◽  
pp. 762
Author(s):  
Sarah Mafi ◽  
Cécile Laroche-Raynaud ◽  
Pauline Chazelas ◽  
Anne-Sophie Lia ◽  
Paco Derouault ◽  
...  
Keyword(s):  
Folate Receptor ◽  
Autosomal Recessive Disorder ◽  
Folate Deficiency ◽  
Severe Form ◽  
Pharmacoresistant Epilepsy ◽  
Pathogenic Variants ◽  
Low Levels ◽  
Magnetic Resonance Imaging Mri ◽  
High Doses ◽  
Cerebral Folate Deficiency

Cerebral folate deficiency (CFD) is a neurological disorder characterized by low levels of 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid (CSF). The prevalence of this autosomal recessive disorder is estimated to be <1/1,000,000. Fifteen different pathogenic variants in the folate receptor 1 gene (FOLR1) encoding the receptor of folate α (FRα) have already been described. We present a new pathogenic variation in the FOLR1 in a childhood-stage patient. We aim to establish the core structure of the FRα protein mandatory for its activity. A three-year-old child was admitted at hospital for a first febrile convulsions episode. Recurrent seizures without fever also occurred a few months later, associated with motor and cognitive impairment. Various antiepileptic drugs failed to control seizures. Magnetic resonance imaging (MRI) showed central hypomyelination and biological analysis revealed markedly low levels of 5-MTHF in CSF. Next generation sequencing (NGS) confirmed a CFD with a FOLR1 homozygous variation (c.197 G > A, p.Cys66Tyr). This variation induces an altered folate receptor α protein and underlines the role of a disulfide bond: Cys66-Cys109, essential to transport 5-MTHF into the central nervous system. Fortunately, this severe form of CFD had remarkably responded to high doses of oral folinic acid combined with intravenous administrations.

scholarly journals Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1508
Author(s):  
Isabelle Jéru ◽  
Amira Nabil ◽  
Gehad El-Makkawy ◽  
Olivier Lascols ◽  
Corinne Vigouroux ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Genetic Disorders ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Partial Lipodystrophy ◽  
Mandibular Hypoplasia ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants ◽  
Mandibuloacral Dysplasia

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations.

scholarly journals An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs

2020 ◽  
Vol 29 (13) ◽  
pp. 2250-2260 ◽  
Author(s):  
Nicola Bedoni ◽  
Mathieu Quinodoz ◽  
Michele Pinelli ◽  
Gerarda Cappuccio ◽  
Annalaura Torella ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Autosomal Recessive Disorder ◽  
Severe Form ◽  
Chromosome 1 ◽  
Whole Genome ◽  
Leber Congenital Amaurosis ◽  
Pathogenic Variants ◽  
Long Read ◽  
Biallelic Mutations

Abstract We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients’ fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. Pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic Leber congenital amaurosis (LCA). However, no patient with null biallelic mutations has ever been described, and murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality.

scholarly journals Case Report: Prenatal Diagnosis of a Fetus With Harlequin Ichthyosis Identifies Novel Compound Heterozygous Variants: A Case Report

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiao Liu ◽  
Xingyu Zhang ◽  
Weilan Wang ◽  
Xiaofang Lan ◽  
Minyue Dong ◽  
...  
Keyword(s):  
Case Report ◽  
Soft Tissues ◽  
Severe Form ◽  
Whole Body ◽  
Chromosomal Microarray ◽  
Compound Heterozygous ◽  
Chromosomal Microarray Analysis ◽  
Pathogenic Variants ◽  
Harlequin Ichthyosis ◽  
Compound Heterozygous Variants

BackgroundHarlequin ichthyosis (HI) is the most severe form of the keratinizing disorders, and it is characterized by whole-body hard stratum corneum. ABCA12 has been identified as the major disease-causing gene of HI.MethodsA case of HI was prenatally diagnosed by ultrasonography and genetic tests. The fetus had been found with dentofacial deformity and profound thickening of the palm and plantar soft tissues. Chromosomal microarray analysis (CMA) and whole exome sequencing (WES) were then performed on the amniotic fluid to identify germline pathogenic variants for the fetus. Candidate variants were verified by Sanger sequencing.ResultsCompound heterozygous frameshift variants (p.Q719QfsX21; p.F2286LfsX6) of ABCA12 were identified for the fetus, suggesting the former variants were maternally inherited and the latter paternally inherited. The fetus was terminated.ConclusionA prenatal molecular diagnosis is an important approach for the prevention of HI. In the study, we provided a successful case of genetic counseling for a family with an HI baby.

The genetics and clinical manifestations of patients with vitamin D dependent rickets type 1A

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ayse Ozden ◽  
Hakan Doneray
Keyword(s):  
Vitamin D ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Treatment Modalities ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Laboratory Findings ◽  
Day Range ◽  
The Mean

Abstract Objectives Vitamin D dependent rickets type 1A (VDDR-1A) is a very rare autosomal recessive disorder caused by mutations in the CYP27B1, which encodes vitamin D 1α-hydroxylase. We report the genetics and clinical manifestations of nine patients with VDDR-1A and compare our patients to other cases with the same mutations in the literature. Methods The clinical presentations, clinical and laboratory findings and treatment modalities of the patients were evaluated retrospectively. Results The mean age of the patients at the time of diagnosis was 39.9 months (range: 4.5–111). At the time of diagnosis, six patients had received stoss vitamin D therapy. Clinical findings related to rickets were obvious in seven patients and unclear in two patients. Except for one case, all patients had laboratory findings of rickets. A novel variant and four previously reported mutations in CYP27B1 were identified. The mean calcitriol and elemental calcium dose were 45.5 ng/kg/day (range: 20–70) and 75.6 mg/kg/day (range: 45–125), respectively. Conclusions We found a novel compound heterozygous mutation consisting of a reported duplication [(p.F443Pfs*24 (c.1319_1325 dup CCCACCC)] in exon 8 and a novel deletion [p.D507Efs*34 (c.1521 delC)] in exon 9. Our study suggests that the clinical manifestations and laboratory findings of the patients with VDDR1A are variable even among the patients with the same mutation.

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