MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome).

BACKGROUND: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs. OBJECTIVE: A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families. RESULTS: We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly. CONCLUSION: This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway

Primary cilia-regulated transcriptome in the renal collecting duct

Contains fulltext : 192636.pdf (publisher's version ) (Closed access

Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer-Saldino syndrome diagnosis

Contains fulltext : 199977.pdf (publisher's version ) (Open Access)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: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Methods: We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Results: Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. Conclusions: By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer-Saldino syndrome, caused by variants in IFT140. We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing

Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects

Contains fulltext : 199518.pdf (Publisher’s version ) (Open Access

Trombose venosa dos membros superiores Venous thrombosis of the upper limbs

Foi realizada uma revisão da evolução clínica de 52 pacientes portadores de trombose venosa axilar e/ou subclávia. Na opinião do autor, até o presente não se tem evidência do esforço na patogenia dessa forma topográfica de trombose venosa. A terminologia síndrome de Paget-Schrötter pode ser usada quando existe um trombo, conforme sugeriram esses autores. No que diz respeito aos pacientes cujo quadro clínico têm como fator preponderante uma compressão extrínseca dos troncos venosos, deve-se levar em consideração uma outra síndrome, como a do desfiladeiro torácico. Para a confirmação de uma suspeita clínica de trombose venosa profunda, a flebografia é o padrão-ouro. O tratamento ideal da oclusão venosa axilo-subclávia não foi ainda estabelecido, mas o anticoagulante tem a preferência. A eficácia do efeito trombolítico in situ é contestada em publicações da literatura médica. O acesso cirúrgico direto para a trombectomia pode ser feito somente em condições especiais.<br>Clinical course of 52 patients with axillary and/or subclavian vein thrombosis was reviewed. In the author's opinion, up to the present time we have no evidence of strain in the pathogenesis of this topographic vein thrombosis. The term Paget-Schrötter syndrome can be used when a thrombus is present, as these authors have suggested. With regard to the patients whose clinical picture is supported by an extrinsic compression on the venous trunks, another syndrome must be considered, such as the thoracic outlet syndrome. For the determination of a clinically suspected deep venous thrombosis, phlebography is the gold standard. The optimal treatment for the axillary-subclavian venous occlusion remains to be established, but the anticoagulant therapy has the preference. The efficacy of in situ thrombolytic effect is contested in medical publications. A direct surgical access for thrombectomy can be made only under special conditions