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Background Distal renal tubular acidosis (RTA) is typically caused by defects in ATP6V0A4, ATP6V1B1, and SLC4A1, accounting for 60-80% of patients. Genes recently implicated include FOXI1, ATP6V1C2, and WDR72, of which WDR72 is associated with dental enamel defects. Methods We describe 4 patients, from three unrelated consanguineous families, with RTA and amelogenesis imperfecta. Distal tubular acidification was evaluated by furosemide-fludrocortisone test, urine-to-blood PCO2 gradient and fractional excretion of bicarbonate. Exome sequencing was performed using a panel of genes implicated in human disease. Results Patients had polyuria, hypokalemia, hypercalciuria, and nephrocalcinosis, but metabolic acidosis varied in severity. Although all patients acidified urine to pH < 5.3 during furosemide-fludrocortisone test, urine-to-blood PCO.sub.2 gradient was < 20 mmHg during bicarbonate loading. All patients had transient proximal tubular dysfunction with urinary losses of phosphate and beta-2-microglobulin, and generalized aminoaciduria. Homozygous pathogenic truncating variants in WDR72 was detected in all probands. Conclusion Patients with WDR72 mutations show mild rate-dependent distal RTA with variable metabolic acidosis, and intact ability to acidify the urine on provocative testing. Concomitant proximal tubular dysfunction may be present. Mutations in WDR72 should be considered in patients with suspected distal RTA, especially if associated with dental defects., Author(s): Priyanka Khandelwal [sup.1] Mahesh V [sup.1] , Vijay Prakash Mathur [sup.2] , Sumantra Raut [sup.1] , Thenral S. Geetha [sup.3] , Sandhya Nair [sup.3] , Pankaj Hari [sup.1] , [...]

Background: Recent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome‐wide association study (GWAS) identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused. Objective: The aim was to identify genetic risk factors for PD in a South Asian population. Methods: A total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early‐onset PD) were recruited from 10 specialty movement disorder centers across India over a 2‐year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case‐only and case–control genetic analyses for PD diagnosis and AoO. Results: A genome‐wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease. Conclusions: This study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Filaggrin (FLG) gene encoding the protein filaggrin plays an important role in barrier function of the skin and its alteration is a predisposing factor for atopic dermatitis. FLG gene variants result in absent or decreased filaggrin protein. Worldwide, the prevalence of FLG variants ranges from 14 to 56%. FLG null variants are distinct in each population. Objectives: To study the FLG gene polymorphisms in Indian children and attempt a genotype-phenotype correlation in atopic dermatitis. Methods: This was a cross-sectional, multicentre study conducted on 75 Indian children. Demographic details, clinical features and identified FLG null variants were recorded. We performed a whole gene sequencing of the entire FLG coding region using next-generation sequencing technology. Results: The prevalence of FLG null variants was 34.7%. A total of 20 different FLG loss of function variants in 26 children were documented. Sixteen (80%) variants were novel and four (20%) were previously reported in Asian and European populations. We found a statistically significant association between FLG variants with early age of onset of atopic dermatitis (P = 0.016) and elevated serum IgE levels (P = 0.051). There was no significant difference between atopic dermatitis phenotypes in children having one variant as compared to children harbouring two or more null variants. Limitations: Small sample size. Conclusion: Our study reports a unique set of FLG variants different from Asian and European populations, with these variants being significantly associated with an early age of onset of atopic dermatitis and elevated serum IgE levels. [ABSTRACT FROM AUTHOR]

Background Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus. Methods Detailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents. Results 24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously. Conclusion This large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare 'Golgipathies'. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a girl with skeletal dysplasia, a condition characterized by abnormal bone development. The girl presented with poor height and weight gain, as well as various physical abnormalities such as macrocephaly, depressed nasal bridge, and short limbs. Genetic analysis revealed a novel mutation in the PRKG2 gene, which is associated with a rare form of acromesomelic dysplasia. The study highlights the importance of animal models in identifying disease genes and suggests that certain MAPK inhibitors may be suitable for treating skeletal dysplasia. [Extracted from the article]

Abstract: Background: Several genes have been implicated in a highly variable presentation of developmental delay with psychomotor retardation. Mutations in EMC1 gene have recently been reported. Herein, we describe a proband born of a consanguineous marriage, who presented with early infantile onset epilepsy, scaphocephaly, developmental delay, central hypotonia, muscle wasting, and severe cerebellar and brainstem atrophy. Methods: Genetic testing in the proband was performed using custom clinical exome and targeted next‐generation sequencing. This was followed by segregation analysis of the variant in the parents by Sanger sequencing and evaluation of the splice variant by RNA sequencing. Results: Clinical exome sequencing identified a novel homozygous intronic splice variant in the EMC1 gene (chr1:19564510C>T, c.1212 + 1G>A, NM_015047.2). Neither population databases (ExAC and 1000 genomes) nor our internal database (n = 1,500) had reported this rare variant, predicted to affect the splicing. RNA sequencing data from the proband confirmed aberrant splicing with intron 11 retention, thereby introducing a stop codon in the resultant mRNA. This nonsense mutation is predicted to result in the premature termination of protein synthesis leading to loss of function of the EMC1 protein. Conclusion: We report, for the first time the role of aberrant EMC1RNA splicing as a potential cause of disease pathogenesis. The severe epilepsy observed in our study expands the disease‐associated phenotype and also emphasizes the need for comprehensive screening of intronic splice mutations. [ABSTRACT FROM AUTHOR]

ABSTRACT We report a novel missense mutation (c.1040 G> A, p. Arg347 Gln) in MID2, which encodes ubiquitin ligase E3, as the likely cause of X-linked mental retardation in a large kindred. The mutation was observed in all affected and obligate carriers but not in any unaffected males of the family or in population controls ( n = 200). When transiently expressed in HEK293T cell line, the mutation was found to abolish the function of the COS domain in the protein. The GFP-tagged mutant protein accumulated in the cytoplasm instead of binding to the cytoskeleton resulting in its altered subcellular localization. Screening of coding exons of this gene in additional 480 unrelated individuals with idiopathic intellectual disability identified another novel variation p. Asn343 Ser. This study highlights the growing role of the ubiquitin pathway in intellectual disability and also, the difference in MID2 determined phenotype observed in this study compared with that of its paralogue MID1 reported in literature. [ABSTRACT FROM AUTHOR]

Keywords: familial CJD; fatal familial insomnia EN familial CJD fatal familial insomnia 164 165 2 01/06/21 20210101 NES 210101 Baldelli et al.1 raise an important issue in respect to our report of a 54 year old man with D178N mutation in PRNP gene presenting with rapidly progressive autosomal dominant ataxia and vocal cord palsy.2 The D178N mutation in PRNP gene can have two phenotypic presentations - Fatal familial insomnia (FFI) or Creutzfeldt-Jacob Disease (CJD). The proband had heterozygous missense mutation in PRNP gene (D178N), which is common to CJD and FFI. A case of autosomal dominant ataxia with vocal cord palsy attributed to a mutation in the PRNP gene. [Extracted from the article]

Highlights from the article: The first report identifying GNAL mutation included 28 dystonia patients from eight families who had predominantly craniocervical form of dystonia with onset of symptom typically in the neck [[1]]. Recently, Sarva et al. also published a study describing three dystonia patients with GNAL mutation and all had amelioration of severe cervical dystonia symptoms after DBS; although cranial (including speech) and limb dystonia did not improve [[5]].