scholarly journals Spondyloocular Syndrome: A Novel XYLT2 Variant with Description of the Neonatal Phenotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Gabriella Doddato ◽  
Alessandra Fabbiani ◽  
Chiara Fallerini ◽  
Mirella Bruttini ◽  
Theodora Hadjistilianou ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Phenotypic Variability ◽  
Autosomal Recessive Inheritance ◽  
Nuchal Translucency ◽  
Gene Encoding ◽  
Nasal Bridge ◽  
Facial Profile ◽  
Pathogenic Variants ◽  
Skeletal Defects ◽  
Bone Abnormalities

Spondyloocular syndrome (SOS) is a skeletal disorder caused by pathogenic variants in XYLT2 gene encoding a xylotransferase involved in the biosynthesis of proteoglycans. This condition, with autosomal recessive inheritance, has a high phenotypic variability. It is characterized by bone abnormalities (osteoporosis, fractures), eye and cardiac defects, hearing impairment, and varying degrees of developmental delay. Until now only 20 mutated individuals have been reported worldwide. Here, we describe two siblings from consanguineous healthy parents in which a novel homozygous frameshift variant c.1586dup p(Thr530Hisfs*) in the XYLT2 gene was detected by exome sequencing (ES). The first patient (9 years) presented short stature with skeletal defects, long face, hearing loss and cataract. The second patient, evaluated at a few days of life, showed macrosomia, diffuse hypertrichosis on the back, overabundant skin in the retronucal area, flattened facial profile with drooping cheeks, elongated eyelid rims, wide and flattened nasal bridge and turned down corners of the mouth. During the prenatal period, high nuchal translucency and intestinal hyperechogenicity were observed at ultrasound. In conclusion, these two siblings with a novel pathogenic variant in XYLT2 further expand the clinical and mutational spectrum of SOS.

scholarly journals Identification of two novel pathogenic variants of PIBF1 by whole exome sequencing in a 2-year-old boy with Joubert syndrome

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yue Shen ◽  
Hao Wang ◽  
Zhimin Liu ◽  
Minna Luo ◽  
Siyu Ma ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Autosomal Recessive Inheritance ◽  
Joubert Syndrome ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Syndrome Individual

Abstract Background Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes. Case presentation A two-year-old boy was diagnosed with Joubert syndrome by global development delay and molar tooth sign of mid-brain. Whole exome sequencing was performed to detect the causative gene variants in this individual, and the candidate pathogenic variants were verified by Sanger sequencing. We identified two pathogenic variants (NM_006346.2: c.1147delC and c.1054A > G) of PIBF1 in this Joubert syndrome individual, which is consistent with the mode of autosomal recessive inheritance. Conclusion In this study, we identified two novel pathogenic variants in PIBF1 in a Joubert syndrome individual using whole exome sequencing, thereby expanding the PIBF1 pathogenic variant spectrum of Joubert syndrome.

scholarly journals PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1489
Author(s):  
Gabriela Rudd Garces ◽  
Maria Elena Turba ◽  
Myriam Muracchini ◽  
Alessia Diana ◽  
Vidhya Jagannathan ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Donor Site ◽  
Genetic Defect ◽  
Autosomal Recessive Inheritance ◽  
Homozygosity Mapping ◽  
Splice Donor Site ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Encoding Protein

Dwarfism phenotypes occur in many species and may be caused by genetic or environmental factors. In this study, we investigated a family of nine Dogo Argentino dogs, in which two dogs were affected by disproportionate dwarfism. Radiographs of an affected dog revealed a decreased level of endochondral ossification in its growth plates, and a premature closure of the distal ulnar physes. The pedigree of the dogs presented evidence of monogenic autosomal recessive inheritance; combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 34 genome segments, totaling 125 Mb. The genome of an affected dog was sequenced and compared to 795 control genomes. The prioritization of private variants revealed a clear top candidate variant for the observed dwarfism. This variant, PRKG2:XM_022413533.1:c.1634 + 1G>T, affects the splice donor site and is therefore predicted to disrupt the function of the PKRG2 gene encoding protein, kinase cGMP-dependent type 2, a known regulator of chondrocyte differentiation. The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs. PRKG2 loss-of-function variants were previously reported to cause disproportionate dwarfism in humans, cattle, mice, and rats. Together with the comparative data from other species, our data strongly suggest PRKG2:c.1634+1G>T to be a candidate causative variant for the observed dwarfism phenotype in Dogo Argentino dogs.

scholarly journals Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors

2020 ◽  
Vol 21 (23) ◽  
pp. 9016
Author(s):  
Emanuele Bellacchio
Keyword(s):  
Structural Damage ◽  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Molecular Characteristics ◽  
Healthy Population ◽  
Pathogenic Mechanisms ◽  
Recessive Mutations ◽  
Pathogenic Variants ◽  
Variant Frequency ◽  
Disease Inheritance

Different pathogenic variants in the same protein or even within the same domain of a protein may differ in their patterns of disease inheritance, with some of the variants behaving as negative dominant and others as autosomal recessive mutations. Here is presented a structural analysis and comparison of the molecular characteristics of the sites in fibrinogen γ-module, a fibrinogen component critical in multimerization processes, targeted by pathogenic variants (HGMD database) and by variants found in the healthy population (gnomAD database). The main result of this study is the identification of the molecular pathogenic mechanisms defining which pattern of disease inheritance is selected by mutations at the crossroad of autosomal recessive and negative dominant modalities. The observations in this analysis also warn about the possibility that several variants reported in the non-pathogenic gnomAD database might indeed be a hidden source of diseases with autosomal recessive inheritance or requiring a combination with other disease-causing mutations. Disease presentation might remain mostly unrevealed simply because the very low variant frequency rarely results in biallelic pathogenic mutations or the coupling with mutations in other genes contributing to the same disease. The results here presented provide hints for a deeper search of pathogenic mechanisms and modalities of disease inheritance for protein mutants participating in multimerization phenomena.

scholarly journals SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia

2020 ◽  
Vol 6 (4) ◽  
pp. e478 ◽  
Author(s):  
Tommy Stödberg ◽  
Måns Magnusson ◽  
Nicole Lesko ◽  
Anna Wredenberg ◽  
Daniel Martin Munoz ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Autosomal Recessive Inheritance ◽  
Recessive Inheritance ◽  
Inheritance Pattern ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Gastrointestinal Problems ◽  
Life Threatening

ObjectiveTo describe the phenotype in 2 sisters with a rare constellation of neurologic symptoms and secretory impairments and to identify the etiology by the use of whole-genome sequencing (WGS).MethodsAfter an extensive workup failed to reveal the cause of disease, in a girl with a previously not reported phenotype, WGS of the proband, her diseased older sister, an older healthy brother, and their parents was performed, and potentially pathogenic variants were analyzed.ResultsThe proband and her older sister both presented with neonatal Staphylococcus aureus parotitis, apneas, disappearance of the Moro reflex, and hypotonia. The proband survived. Her brain MRI showed white matter and basal ganglia abnormalities, and CSF damage biomarkers were increased. At age 8 years, she exhibits a constellation of symptoms including severe neurodevelopmental disorder, hearing impairment, gastrointestinal problems, and a striking lack of tear fluid, saliva, and sweat. Her respiratory mucosa is dry with potentially life-threatening mucus plugging. Through WGS, 2 loss-of-function variants in SLC12A2 were identified that follow an autosomal recessive inheritance pattern.ConclusionsTaken together with a single previously reported case and the close resemblance to the phenotypes of corresponding mouse models, our study firmly establishes biallelic variants in SLC12A2 as causing human disease and adds data regarding the neurologic phenotype.

scholarly journals A Novel GDAP1 Mutation P78L Responsible for CMT4A Disease in Three Moroccan Families

2007 ◽  
Vol 34 (4) ◽  
pp. 421-426 ◽  
Author(s):  
Ahmed Bouhouche ◽  
Nazha Birouk ◽  
Ali Benomar ◽  
Reda Ouazzani ◽  
Taïeb Chkili ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Disease Duration ◽  
Common Ancestor ◽  
Founder Mutation ◽  
Autosomal Recessive Inheritance ◽  
Compound Heterozygous ◽  
Common Haplotype ◽  
Gene Encoding ◽  
Gene Coding ◽  
Different Origins

Background:The gene encoding the ganglioside-induced-differentiation-associated protein 1 (GDAP1) has been associated with both axonal and demyelinating neuropathy. Up to date, 25 mutations in the GDAP1 gene have been reported in patients from different origins.Methods:Three Moroccan families with early onset ARCMT1 and autosomal recessive inheritance were genotyped to test linkage to 8q21.3 and their GDAP1 gene coding exons screened for mutations.Results:A novel C233T transversion at codon 78 (P78L) was detected in 6 patients from 3 unrelated families. The mutation was found to be homozygous in two families and compound heterozygous in association with the already reported S194X mutation in one family. The P78L mutation was associated with a common haplotype suggesting a Moroccan founder mutation. The patients had symptoms within the two first years of life and developed common phenotype of CMT4A with evident hoarse-voice in two cases with the longer disease duration.Conclusion:P78L mutation was associated with a common haplotype suggesting a common ancestor.

scholarly journals Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 149
Author(s):  
María Domínguez-Ruiz ◽  
Montserrat Rodríguez-Ballesteros ◽  
Marta Gandía ◽  
Elena Gómez-Rosas ◽  
Manuela Villamar ◽  
...  
Keyword(s):  
Hearing Impairment ◽  
Autosomal Recessive ◽  
Auditory Neuropathy ◽  
Spectrum Disorder ◽  
Gene Encoding ◽  
Auditory Neuropathy Spectrum Disorder ◽  
Familial Cases ◽  
Pathogenic Variants ◽  
Cochlear Hearing Loss ◽  
Syndromic Hearing Impairment

Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.

Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form

2021 ◽  
Vol 14 (1) ◽  
pp. e236732
Author(s):  
Weiyi Mu ◽  
Teresa Heller ◽  
Kristin W Barañano
Keyword(s):  
Autosomal Recessive ◽  
Phenotypic Variability ◽  
Compound Heterozygous ◽  
Pontocerebellar Hypoplasia ◽  
Neurocognitive Impairments ◽  
Pathogenic Variants ◽  
Novel Variant ◽  
A Subunit ◽  
Rna Exosome ◽  
Exosome Complex

Pontocerebellar hypoplasia type 1B (PCH1B) describes an autosomal recessive neurological condition that involves hypoplasia or atrophy of the cerebellum and pons, resulting in neurocognitive impairments. Although there is phenotypic variability, this is often an infantile lethal condition, and most cases have been described to be congenital and neurodegenerative. PCH1B is caused by mutations in the gene EXOSC3, which encodes exosome component 3, a subunit of the human RNA exosome complex. A range of pathogenic variants with some correlation to phenotype have been reported. The most commonly reported pathogenic variant in EXOSC3 is c.395A>C, p.(Asp132Ala); homozygosity for this variant has been proposed to lead to milder phenotypes than compound heterozygosity. In this case, we report two siblings with extraordinarily mild presentations of PCH1B who are compound heterozygous for variants in EXOSC3 c.155delC and c.80T>G. These patients drastically expand the phenotypic variability of PCH1B and raise questions about genotype–phenotype associations.

scholarly journals A Compound Heterozygous Mutation in the Ciliary Gene TTC21B Causes Nephronophthisis Type 12

2019 ◽  
Vol 09 (03) ◽  
pp. 198-202
Author(s):  
Wafaa Moustafa M. Abo El Fotoh ◽  
Amira Fathy Al-fiky
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Renal Disorder ◽  
Pathogenic Variants ◽  
Tubulointerstitial Lesions ◽  
Stage Renal Disease ◽  
End Stage

AbstractNephronophthisis (NPHP) is one of the renal ciliopathies and is also a cystic renal disorder with an autosomal recessive inheritance, which usually progresses to end-stage renal disease (ESRD). It affects children, adolescents, and young adults. In approximately 15% of cases, the features of a ciliopathy syndrome, which include liver fibrosis, skeletal anomalies, retinal abnormalities, and neurodevelopmental delay, will be present. We describe a case of a 2-year-old male child with ESRD on hemodialysis and a family record of a similar condition (his brother). The clinical features of this child are succinctly summarized. The genetic study was conducted using whole exome sequencing. TTC21B mutational variants were detected in our patient who exhibited nephrotic-range proteinuria, focal segmental glomerulosclerosis, and tubulointerstitial lesions that evolved to ESRD. Compound heterozygous mutations, c.626c > t (p.P209L) in exon 6 and c.450 g > a (p.W150Ter) in exon 5, were uncovered. These findings are in line with the description of autosomal recessive NPHP type 12. Both clinical and pathological diagnoses of NPHP are critical, bearing in mind ESRD as well as its related extrarenal defining features. Identification of the pathogenic variants in the TTC21B gene assisted in the successful proof of the clinical diagnosis NPHP12 as well as providing information for formal suitable prenatal counseling.

Pelizaeus Merzbacher phenotype with epilepsy and autosomal recessive inheritance in two siblings

2006 ◽  
Vol 37 (03) ◽  
Author(s):  
U Gaiser ◽  
J Neuberger ◽  
E Regel ◽  
R Emmert ◽  
M Ries
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Recessive Inheritance
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