Complexome profiling showed impaired immunoproteasome assembly in a novel PRAAS subtype caused by monoallelic PSMB8 variants.

Immunoproteasomes, essential for MHC class I antigen presentation, differ from standard proteasomes by incorporating the catalytic subunits PSMB9 (β1i), PSMB10 (β2i), and PSMB8 (β5i). Proteasome-associated autoinflammatory syndromes (PRAAS) are type I interferonopathies resulting from impaired proteasome function. Here, we describe two individuals carrying monoallelic variants in , both presenting with early-onset systemic autoinflammation and features of immunodeficiency, accompanied by a marked type I interferon response.

Missense variants in cause myo-tubulinopathies.

Tubulinopathies encompass a wide spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked or dominantly inherited missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, hereditary spastic ataxia, and more recently, an isolated report of congenital myopathy, the full phenotypic and genotypic spectrum of -related disorders remains incompletely characterised. In this multi-centre study, we identified 13 novel missense variants in 31 individuals from 19 unrelated families.

Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.

Purpose: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants.

Inherited Dyslipidemic Splenomegaly: A Genetic Macrophage Storage Disorder Caused by Disruptive Apolipoprotein E () Variants.

Background: Persistent splenomegaly, often an incidental finding, can originate from a number of inherited metabolic disorders (IMDs). Variants of are primarily known as risk factors in terms of cardiovascular disease; however, severe dysfunction of APOE can result in a disease phenotype with considerable overlap with lysosomal storage disorders (LSDs), including splenomegaly and gross elevation of N-palmitoyl-O-phosphocholine-serine (PPCS).

Methods: A case study (deep phenotyping, genetic and FACS analysis) and literature study was conducted.

Variants in , a component of the WASH complex, cause short stature, variable neurodevelopmental abnormalities, and distinctive facial dysmorphism.

Purpose: Genetic defects that impair growth plate chondrogenesis cause a phenotype that varies from skeletal dysplasia to mild short stature with or without other syndromic features. In many individuals with impaired skeletal growth, the genetic causes remain unknown.

Method: Exome sequence was performed in 3 unrelated families with short stature, distinctive facies, and neurodevelopmental abnormalities.

Utilization of automated cilia analysis to characterize novel INPP5E variants in patients with non-syndromic retinitis pigmentosa.

INPP5E encodes inositol polyphosphate-5-phosphatase E, an enzyme involved in regulating the phosphatidylinositol (PIP) makeup of the primary cilium membrane. Pathogenic variants in INPP5E hence cause a variety of ciliopathies: genetic disorders caused by dysfunctional cilia. While the majority of these disorders are syndromic, such as the neuronal ciliopathy Joubert syndrome, in some cases patients will present with an isolated phenotype-most commonly non-syndromic retinitis pigmentosa (RP).

Ciliary phenotyping in renal epithelial cells in a cranioectodermal dysplasia patient with variants.

Cranioectodermal dysplasia (CED) is a skeletal autosomal recessive ciliopathy. The characteristic clinical features of CED are facial dysmorphisms, short limbs, narrow thorax, brachydactyly, ectodermal abnormalities, and renal insufficiency. Thus far, variants in six genes are known to be associated with this disorder: , , , , , and .

Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc).

Identical Variants Cause Variable Skeletal Ciliopathy Phenotypes-Challenges for the Accurate Diagnosis.

Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant phenotypic overlap are known as skeletal ciliopathies and include Jeune asphyxiating thoracic dysplasia (JATD), Mainzer-Saldino syndrome (MZSDS), cranioectodermal dysplasia (CED), and short-rib polydactyly (SRP). Ciliopathies are heterogeneous disorders with >187 associated genes, of which some genes are described to cause more than one ciliopathy phenotype.

Interfamilial clinical variability in four Polish families with cranioectodermal dysplasia and identical compound heterozygous variants in WDR35.

Cranioectodermal dysplasia (CED) is a rare autosomal recessive disorder primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. CED is a chondrodysplasia, which is part of a spectrum of clinically and genetically heterogeneous diseases that result from disruptions in cilia. Pathogenic variants in genes encoding components of the ciliary transport machinery are known to cause CED.

Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease.

Background: Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder.

Cellular ciliary phenotyping indicates pathogenicity of novel variants in and confirms a Mainzer-Saldino syndrome diagnosis.

Background: Mainzer-Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: and .

The KOUNCIL Consortium: From Genetic Defects to Therapeutic Development for Nephronophthisis.

Nephronophthisis (NPH) is the most common monogenic cause of renal failure in children. Treatment options are limited to dialysis and transplantation. Therapeutics to significantly delay or prevent end-stage renal disease (ESRD) in children are currently not available.

Missense mutations in the WD40 domain of cause non-syndromic retinitis pigmentosa.

Background: Recent findings suggesting that () is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether variants cause non-syndromic retinitis pigmentosa (RP).

Methods: Exome sequencing was performed in three probands with RP.

Ciliopathies: Genetics in Pediatric Medicine.

, which are also referred to as , are a group of hereditary disorders that result from dysfunctional cilia. The latter are cellular organelles that stick up from the apical plasma membrane. Cilia have important roles in signal transduction and facilitate communications between cells and their surroundings.

Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes.

A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome.

Background: Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome.

De novo 14q24.2q24.3 microdeletion including IFT43 is associated with intellectual disability, skeletal anomalies, cardiac anomalies, and myopia.

We report an 11-year-old girl with mild intellectual disability, skeletal anomalies, congenital heart defect, myopia, and facial dysmorphisms including an extra incisor, cup-shaped ears, and a preauricular skin tag. Array comparative genomic hybridization analysis identified a de novo 4.5-Mb microdeletion on chromosome 14q24.