Self-limited focal epilepsy and childhood apraxia of speech with WAC pathogenic variants.

Heterozygous pathogenic WAC variants cause Desanto-Shinawi syndrome; affected patients have dysmorphic features, developmental impairment and behavioral abnormalities. Seizures are reported in one quarter, including tonic-clonic, absence, and febrile seizures. This study aimed to better understand the phenotypic spectrum of epilepsy and development in Desanto-Shinawi syndrome.

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.

Correction: A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

The original version of this Article contained an error in the spelling of the author Siddharth Banka, which was incorrectly given as Siddhart Banka. This has now been corrected in both the PDF and HTML versions of the Article.

A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

Purpose: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.

Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish.

The large majority of cases of the autosomal dominant human disease fibrodysplasia ossificans progressiva (FOP) are caused by gain-of-function Arg206His mutations in the BMP type I receptor ACVR1 (ALK2). The Arg206His mutation is located in the GS domain of the type I receptor. This region is normally phosphorylated by the BMP type II receptor, which activates the type I receptor to phosphorylate its substrate, the signal transducer Smad1/5/8.

Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly.

Background: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), a disorder characterised by the development of hamartomas or benign tumours in various organs as well as the variable presence of epilepsy, intellectual disability (ID) and autism. TSC1, TSC2 and the recently described protein TBC1D7 form a complex that inhibits mTORC1 signalling and limits cell growth. Although it has been proposed that mutations in TBC1D7 might also cause TSC, loss of its function has not yet been documented in humans.

Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome.

Mutations in the gene encoding podocin (NPHS2) cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS). For addressing the possibility of a genotype-phenotype correlation between podocin mutations and age of onset, a worldwide cohort of 430 patients from 404 different families with SRNS were screened by direct sequencing. Recessive podocin mutations were present in 18.

Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis.

Recessive NPHS2 (podocin) mutations account for up to approximately 30% of steroid-resistant idiopathic FSGS in children and are associated with a reduced risk for disease recurrence after renal transplantation. R229Q, a missense variant that is present in 3.6% of the white population, has been implicated as a common disease-causing mutation.

Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).

Objectives: Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations.

Mutational analysis of NPHS2 and WT1 in frequently relapsing and steroid-dependent nephrotic syndrome.

Idiopathic nephrotic syndrome is a common pediatric kidney disease, 80% of all cases are steroid sensitive (SSNS). A significant proportion of children with SSNS will have a frequently relapsing or steroid-dependent course (FRNS/SDNS) that is associated with significant treatment-related morbidity. Mutations in NPHS2 account for more than 28% of all cases of steroid-resistant nephrotic syndrome (SRNS) and dominant mutations in WT1 for 5%; while mutations are absent from children with uncomplicated SSNS.

Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.

Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS).

Medullary cystic kidney disease type 1: mutational analysis in 37 genes based on haplotype sharing.

Medullary cystic kidney disease type 1 (MCKD1) is an autosomal dominant, tubulo-interstitial nephropathy that causes renal salt wasting and end-stage renal failure in the fourth to seventh decade of life. MCKD1 was localized to chromosome 1q21. We demonstrated haplotype sharing and confirmed the telomeric border by a recombination of D1S2624 in a Belgian kindred.

Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9.

Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. Approximately 10-25% of familial and sporadic cases are caused by mutations in NPHS2 (podocin). Mutations in exons 8 and 9 of the WT1 gene have been found in patients with isolated SRNS and in SRNS associated with Wilms' tumor (WT) or urogenital malformations.

No evidence for genotype/phenotype correlation in NPHS1 and NPHS2 mutations.

Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. In 26% of cases it is caused by recessive mutations in NPHS2 (podocin). Congenital nephrotic syndrome (CNS) is caused by mutations in NPHS1 (nephrin) or NPHS2.

Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome.

Background: Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant nephrotic syndrome (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes for end-stage renal disease (ESRD) in the first two decades of life.

Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life.

Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains.

Background: Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulointerstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. The chromosomal locus for MCKD2 was localized on chromosome 16p12. Within this chromosomal region, Uromodulin (UMOD) was located as a candidate gene.