scholarly journals Acute recurrent rhabdomyolysis in a Chinese boy associated with a novel compound heterozygous LPIN1 variant: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ke Tong ◽  
Geng-Sheng Yu
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Serum Creatine Kinase ◽  
Accurate Diagnosis ◽  
Strenuous Exercise ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Heterozygous Variant ◽  
Recurrent Rhabdomyolysis

Abstract Background LPIN1-related acute recurrent rhabdomyolysis (RM), first reported in 2008, is an autosomal recessive inherited metabolic disease. In recent years, LPIN1 gene variants have been identified as one of the main causes of severe RM in children in Western countries. The disease is extremely rare in China, and we report a case of acute recurrent RM caused by a novel compound heterozygous LPIN1 variant. Case presentation A 15-year-old Chinese boy presented with myalgia after strenuous exercise, accompanied by transient increases in serum creatine kinase and myoglobin and persistent hyperuricaemia and hyperbilirubinaemia. Genetic analysis using high-throughput genomic sequencing and Sanger sequencing revealed that there was a compound heterozygous variant in the LPIN1 gene of the proband: the paternal c.2047A > G(p.I683V) was an unreported missense variant, and the maternal c.2107_2108 insAGG(p.Q703delin sQE) was an unreported in-frame variant. Conclusions In children with RM, LPIN1 variants should always be considered in the differential diagnosis. The clinical features of our case are atypical, which highlights the importance of an accurate diagnosis by genetic testing. If detected early, the condition may be controlled, and the prognosis may be improved.

3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Radha Rama Devi Akella
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Whole Exome ◽  
Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

scholarly journals Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Sha Zhao ◽  
Zhenqing Luo ◽  
Zhenghui Xiao ◽  
Liping Li ◽  
Rui Zhao ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Chinese Population ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Cohen Syndrome ◽  
The Family ◽  
Sporadic Cases

Abstract Background Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China. Case presentation A Chinese family with two offspring–patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly. Conclusions This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.

scholarly journals Case Report: Clinical Features of Childhood Leukoencephalopathy With Cerebral Calcifications and Cysts Due to SNORD118 Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong Jin ◽  
Xiaotun Ren ◽  
Husheng Wu ◽  
Yanqi Hou ◽  
Fang Fang
Keyword(s):  
Autosomal Recessive ◽  
Age At Onset ◽  
Compound Heterozygous ◽  
Protein Coding ◽  
Case Presentation ◽  
Cerebral Calcifications ◽  
Clinical Investigations ◽  
Patient Reported ◽  
Cerebral Microangiopathy ◽  
Compound Heterozygous Variants

Background: Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a rare autosomal recessive cerebral microangiopathy. Recently, biallelic variants in a non-protein-coding gene SNORD118 have been discovered to cause LCC.Case Presentation: We here report a genetically confirmed childhood case of LCC. The patient was a 4-year-and-1-month-old boy with focal seizures. The age at onset of his seizure was 10 days after birth. The seizures were well-controlled by antiepileptic treatment but reoccurred twice due to a head impact accident and a fever, respectively. He suffered from a self-limited esotropia and unsteady running gait during the seizure onset. He had the typical neuroimaging triad of multifocal intracranial calcifications, cysts, and leukoencephalopathy. Genetic analysis indicated that he carried compound heterozygous variants of n.*9C>T and n.3C>T in SNORD118, which were inherited from his parents.Conclusion: We report a childhood LCC case with compound heterozygous variants in SNORD118. To the best of our knowledge, the patient reported in our case had the youngest onset age of LCC with a determined genotype. The triad cerebral-imaging findings of calcifications, cysts, and leukoencephalopathy provide a crucial diagnostic basis. Moreover, the gene assessment, together with the clinical investigations, should be considered for the diagnosis of LCC.

scholarly journals An Autosomal Recessive form of Cornelia de Lange Syndrome Due to Mutations in TRMT61A Gene: A Case Report

2020 ◽  
pp. 327-331
Author(s):  
Fadel A. Sharif
Keyword(s):  
Autosomal Recessive ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Cornelia De Lange Syndrome ◽  
Rna Modification ◽  
Compound Heterozygous ◽  
Specific Pcr ◽  
Gastrointestinal Problems ◽  
Cornelia De Lange ◽  
Coding Variants

Background: Cornelia de Lange syndrome is a rare genetic disorder presenting with craniofacial dysmorphia, developmental delay, intellectual disabilities, upper limb abnormalities and gastrointestinal problems. The disease is genetically heterogenous and the underlying genetic cause in unknown in around 30% of the cases. Case Presentation: A Palestinian family visited our department for genetic counseling. The non-consanguineous parents have only two (4 and 2 years old) daughters, both presented with features consistent with Cornelia de Lange syndrome. Whole exome sequencing revealed two previously unknown coding variants in the autosomal TRMT61A, a gene that has not been linked to any human disease before. TRMT61A codes for the catalytic subunit of tRNA (adenine-N1-)-methyltransferase. The mother harbored an in-frame deletion variant c.478_483delCGCACC (p.R160_T161del), whereas the father carried a missense variant c.323G>T (p.C108F). Both variants are novel and were predicted as "damaging". So far, no autosomal recessive forms of the disease has been described in the literature. The carrier states of the parents and the existence of the two variants in compound heterozygous forms in both girls was further confirmed by allele-specific PCR. In their next pregnancy, prenatal diagnosis indicated that the fetus is a carrier of the mother's variant and the pregnancy culminated in the birth of a healthy baby girl. Conclusion: It can be concluded that the TRMT61A mutations are the cause of the disease features observed in this family and supports the proposal that RNA modification defects are involved in the molecular pathogenesis of Cornelia de Lange syndrome.

scholarly journals Variants in the PNPLA1 Gene in Families with Autosomal Recessive Congenital Ichthyosis Reveal Clinical Significance

2021 ◽  
pp. 1-11
Author(s):  
Farooq Ahmad ◽  
Ishtiaq Ahmed ◽  
Qamre Alam ◽  
Tanveer Ahmad ◽  
Ammara Khan ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Sequence Variant ◽  
Phenotype Correlation ◽  
Congenital Ichthyosis ◽  
Whole Exome ◽  
Autosomal Recessive Congenital Ichthyosis

The term autosomal recessive congenital ichthyosis (ARCI) is the subgroup of ichthyosis, which describes a highly heterogeneous group of genetic disorders of the skin characterized by cornification and defective keratinocytes differentiation associated with mutations in at least 14 genes including <i>PNPLA1</i>. To study the molecular basis of the Pakistani kindreds (A and B) affected by ARCI, whole-exome sequencing (WES) in the DNA samples of affected members was performed followed by Sanger sequencing of the candidate gene to hunt down the disease-causing sequence variant/s. WES data analysis led to the identification of a novel nonsense sequence variant (c.892C&#x3e;T; p.Arg298*, family A) and a recurrent missense variant (c.102C&#x3e;A; p.Asp34Glu, family B) in <i>PNPLA1</i> mapped to the ARCI locus in chromosome 6p21.31. Validation and cosegregation analysis of the variants in the remaining family members of the respective families were confirmed by Sanger sequencing. The current investigation expands the spectrum of <i>PNPLA1</i> mutations and helps establish the proper clinico-genetic diagnosis and correct genotype-phenotype correlation.

Exertional rhabdomyolysis in carbonic anhydrase 12 deficiency

2018 ◽  
Vol 31 (6) ◽  
pp. 697-699 ◽  
Author(s):  
Dekel Avital ◽  
Eli Hershkovitz ◽  
Neta Loewenthal
Keyword(s):  
Carbonic Anhydrase ◽  
Autosomal Recessive ◽  
Salt Intake ◽  
Strenuous Exercise ◽  
Salt Precipitation ◽  
Case Presentation ◽  
Salt Wasting ◽  
Exertional Rhabdomyolysis ◽  
Hot Climate ◽  
Recessive Form

Abstract Background: Carbonic anhydrase 12 (CA12) deficiency, a newly recognized rare disorder, has been described among Israeli Bedouin kindred as an autosomal recessive form of isolated salt wasting in sweat, which leads to severe infantile hyponatremic dehydration, visible salt precipitation after sweating, poor feeding and slow weight gain in infancy. Case presentation: We present two adolescents diagnosed with CA12 deficiency who developed severe rhabdomyolysis as a result of physical activity in a hot climate. Conclusions: This presentation highlights a previously unreported but significant clinical complication of this disorder and emphasizes the persistent risk of excessive salt loss via sweat and a need for certain precautions, such as increased salt intake and avoidance of prolonged and/or strenuous exercise.

scholarly journals Novel Missense Mutations in BEST1 Are Associated with Bestrophinopathies in Lebanese Patients

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 151 ◽  
Author(s):  
Lama Jaffal ◽  
Wissam Joumaa ◽  
Alexandre Assi ◽  
Charles Helou ◽  
Christel Condroyer ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Subretinal Fluid ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Autosomal Recessive Bestrophinopathy ◽  
Homozygous Mutations ◽  
Flanking Regions ◽  
Reduced Light ◽  
Exon 10

To identify Bestrophin 1 (BEST1) causative mutations in six Lebanese patients from three families, of whom four had a presumed clinical diagnosis of autosomal recessive bestrophinopathy (ARB) and two showed a phenotype with a single vitelliform lesion, patients were subjected to standard ophthalmic examinations. In addition, BEST1 exons and their flanking regions were amplified and sequenced by Sanger sequencing. Co-segregation and detailed bio-informatic analyses were performed. Clinical examination results were consistent with ARB diagnosis for all index patients showing multifocal vitelliform lesions and a markedly reduced light peak in the electrooculogram, including the two patients with a single vitelliform lesion. In all cases, most likely disease-causing BEST1 mutations co-segregated with the phenotype. The ARB cases showed homozygous missense variants (M1, c.209A>G, p.(Asp70Gly) in exon 3, M2, c.1403C>T; p.(Pro468Leu) in exon 10 and M3, c.830C>T, p.(Thr277Met) in exon 7), while the two patients with a single vitelliform lesion were compound heterozygous for M1 and M2. To our knowledge, this is the first study describing mutations in Lebanese patients with bestrophinopathy, where novel biallelic BEST1 mutations associated with two phenotypes were identified. Homozygous mutations were associated with multifocal lesions, subretinal fluid, and intraretinal cysts, whereas compound heterozygous ones were responsible for a single macular vitelliform lesion.

scholarly journals Two novel compound heterozygous variants of LTBP4 in a Chinese infant with cutis laxa type IC and a review of the related literature

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Qiang Zhang ◽  
Zailong Qin ◽  
Shang Yi ◽  
Hao Wei ◽  
Xun Zhao Zhou ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Retinal Hemorrhage ◽  
Cutis Laxa ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Whole Exome ◽  
Analytical Review ◽  
Different Populations ◽  
Compound Heterozygous Variants ◽  
Chromosome 19Q13

Abstract Background Autosomal recessive cutis laxa type IC (ARCL IC, MIM: #613177) results from a mutation in the LTBP4 gene (MIM: #604710) on chromosome 19q13. Case presentation A 28-day-old Chinese infant with generalized cutis laxa accompanied by impaired pulmonary, gastrointestinal, genitourinary, retinal hemorrhage, abnormality of coagulation and hyperbilirubinemia was admitted to our hospital. To find out the possible causes of these symptoms, whole-exome sequencing was performed on the infant. Two novel pathogenic frame-shift variants [c.605_606delGT (p.Ser204fs * 8) and c.1719delC (p.Arg574fs * 199)] of the LTBP4 gene associated with ARCL IC were found which was later verified by Sanger sequencing. The pathogenicity of mutations was subsequently assessed by several software programs and databases. In addition, an analytical review on the clinical phenotypes of the disease previously reported in literature was performed. Conclusions This is the first report of a Chinese infant with ARCL IC in China due to novel pathogenic variations of LTBP4. Our study extends the cutis laxa type IC mutation spectrum as well as the phenotypes associated with the disease in different populations.

scholarly journals Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Shao-Wen Wu ◽  
Lin Li ◽  
Fan Feng ◽  
Li Wang ◽  
Yuan-Yuan Kong ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Congenital Dislocation ◽  
Case Presentation ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
Dislocation Of The Hip

Abstract Background Wiedemann-Rautenstrauch syndrome (WRS) is a rare autosomal recessive neonatal progeroid disorder characterized by prenatal and postnatal growth retardation, short stature, a progeroid appearance, hypotonia, and mental impairment. Case presentation A 6-year-old patient, who initially presented with multiple postnatal abnormalities, facial dysplasia, micrognathia, skull appearance, hallux valgus, and congenital dislocation of the hip, was recruited in this study. The patient was initially diagnosed with progeria. The mother of the patient had abnormal fetal development during her second pregnancy check-up, and the clinical phenotype of the fetus was similar to that of the patient. Whole-exome sequencing (WES) of the patient was performed, and POLR3B compound heterozygous variants—c.2191G > C:p.E731Q and c.3046G > A:p.V1016M—were identified in the patient. Using Sanger sequencing, we found that the phenotypes and genotypes were segregated within the pedigree. These two variants are novel and not found in the gnomAD and 1000 Genomes databases. The two mutation sites are highly conserved between humans and zebrafish. Conclusions Our study not only identified a novel WRS-associated gene, POLR3B, but also broadened the mutational and phenotypic spectra of POLR3B. Furthermore, WES may be useful for identifying rare disease-related genetic variants.

scholarly journals Evidence for contribution of compound heterozygous variants in Wiskott-Aldrich syndrome like (WASL) gene for early onset Parkinson's disease

2020 ◽  
Author(s):  
Sumeet Kumar ◽  
Masoom M Abbas ◽  
Shyla T Govindappa ◽  
Uday B Muthane ◽  
Sanjay Pandey ◽  
...  
Keyword(s):  
Splice Variant ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Alpha Synuclein ◽  
Compound Heterozygous ◽  
Hek 293 ◽  
Wiskott Aldrich Syndrome ◽  
Functional Characterisation ◽  
Compound Heterozygous Variants

Background: Knowledge of genetic determinants in Parkinsons disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach has been exploited in this study. Methods: Informative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of PD were used for whole exome sequencing. Variant data analysis and in vitro functional characterisation of putative disease causal variant(s) identified thereof were carried out in HEK-293 and SH-SY5Y cells using gene constructs of interest. Results: In a rather uncommon observation, two compound heterozygous variants, a rare missense (c.1139C>T:p.P380L) and a novel splice variant (c.1456+5TAGAG>G) in Wiskott-Aldrich syndrome like gene (WASL, 7q31), both predicted to be deleterious were shared among the proband and her two affected siblings. WASL, a gene hitherto unreported for PD is known to regulate actin polymerisation via Arp2/3 complex. Based on exon trapping assay using pSPL3 vector in HEK-293 cells, the splice variant showed skipping of exon10. Functional characterisation of the missense variant in SH-SY5Y cells demonstrated: i) significant alterations in neurite length and number; ii) decreased ROS tolerance in mutation carrying cells on TBPH induction, and iii) increase in alpha-synuclein protein. Screening for WASL variants in two independent PD cohorts identified four individuals with heterozygous but none with biallelic variants. Conclusion: WASL, with demonstrated functional relevance in neurons may be yet another putative disease causal gene for autosomal recessive PD encouraging assessment of its contribution across populations.

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