Search

P4-ATPases comprise a family of lipid flippases that translocate lipids from the exoplasmic (or luminal) to the cytoplasmic leaflet of biological membranes. Of the 14 known human P4-ATPases, ATP8B2 is a phosphatidylcholine flippase at the plasma membrane, but its physiological function is not well understood. Although ATP8B2 could interact with both CDC50A and CDC50B, it required only the CDC50A interaction for its exit from the endoplasmic reticulum and subsequent transport to the plasma membrane. Three de novo monoallelic missense variations of ATP8B2 were found in patients with intellectual disability. None of these variations affected the interaction of ATP8B2 with CDC50A or its localization to the plasma membrane. However, variations of either of two amino acid residues, which are conserved in all P4-ATPases, significantly reduced the phosphatidylcholine flippase activity of ATP8B2. Furthermore, mutations in the corresponding residues of ATP8B1 and ATP11C were found to decrease their flippase activities toward phosphatidylcholine and phosphatidylserine, respectively. These results indicate that the conserved amino acid residues are crucial for the enzymatic activities of the P4-ATPases. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene. Methods An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/β1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy. Results The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged. Conclusion Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link. [ABSTRACT FROM AUTHOR]

Background: Children with neurodevelopmental disorders (NDDs) often have poor oral health and dental abnormalities. An increasing number of genes have been associated with neurodevelopmental conditions affecting the oral cavity, but the specific dental features associated with many genes remain unknown. Aim: To report the types and frequencies of dental manifestations in children with neurodevelopmental conditions of known genetic cause. Design: A 30‐question survey assesing ectodermal and dental features was administered through Simons Searchlight, with which formed a recontactable cohort of individuals with genetic NDDs often associated with autism spectrum disorder (ASD). Results: Data were collected from a largely paediatric population with 620 affected individuals across 39 genetic conditions and 145 unaffected siblings without NDDs for comparison. Drooling, difficulty accessing dental care, late primary teeth eruption, abnormal primary and permanent teeth formation, misshapen nails, and hair loss were more frequent in individuals with NDDs. Additionally, we evidenced an association between three new pathogenic gene variant/oral manifestation pairs: CSNK2A1/unusual primary teeth, DYRK1A/late primary teeth eruption, and PPP2R5D/sialorrhea. Conclusion: Our results demonstrate that genetic NDDs caused by mutations in CSNK2A1, DYRK1A, and PP2R5D are associated with unique dental manifestations, and knowledge of these features can be helpful to personalize dental care. [ABSTRACT FROM AUTHOR]

In this case study, we report the case of a 13-year-old girl with citrullinemia type 1 (MIM #215700), an autosomal recessive inherited disorder of the urea cycle, which was confirmed by the identification of a homozygous pathogenic variant in the argininosuccinate synthetase 1 (ASS1) gene. However, the patient presented abnormal hyperkinetic movements with global developmental delay and clinical signs that were not fully consistent with those of citrullinemia type 1 or with those of her siblings with isolated citrullinemia type 1. Exome sequencing showed the presence of a de novo heterozygous pathogenic variant in the adenylate cyclase type 5 (ADCY5) gene. The variant confirmed the overlap with the so-called ADCY5-related dyskinesia with orofacial involvement, which is autosomal dominant (MIM #606703), a disorder disrupting the enzymatic conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). In addition to the citrullinemia-related low-protein diet and arginine supplementation, the identification of this second disease led to the introduction of a treatment with caeine, which considerably improved the dyskinesia neurological picture. In conclusion, this case highlights the importance of clinical-biological confrontation for the interpretation of genetic variants, as one hereditary metabolic disease may hide another with therapeutic consequences. Summary: This article reports the misleading superposition of two inherited metabolic diseases, showing the importance of clinical-biological confrontation in the interpretation of genetic variants. [ABSTRACT FROM AUTHOR]

Mitogen‐activated protein kinase 8‐interacting protein 3 gene (MAPK8IP3) encodes the c‐Jun‐amino‐terminal kinase‐interacting protein 3 (JIP3) and is involved in retrograde axonal transport. Heterozygous de novo pathogenic variants in MAPK8IP3 result in a neurodevelopmental disorder with or without brain abnormalities and possible axonal peripheral neuropathy. Whole‐exome sequencing was performed on an individual presenting with severe congenital muscle hypotonia of neuronal origin mimicking lethal spinal muscular atrophy. Compound heterozygous rare variants (a splice and a missense) were detected in MAPK8IP3, inherited from the healthy parents. Western blot analysis in a muscle biopsy sample showed a more than 60% decrease in JIP3 expression. Here, we suggest a novel autosomal recessive phenotype of a lower motor neuron disease caused by JIP3 deficiency. [ABSTRACT FROM AUTHOR]

Deoxyhypusine hydroxylase (DOHH) is the enzyme catalyzing the second step in the post-translational synthesis of hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] in the eukaryotic initiation factor 5A (eIF5A). Hypusine is formed exclusively in eIF5A by two sequential enzymatic steps catalyzed by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Hypusinated eIF5A is essential for translation and cell proliferation in eukaryotes, and all three genes encoding eIF5A, DHPS, and DOHH are highly conserved throughout eukaryotes. Pathogenic variants affecting either DHPS or EIF5A have been previously associated with neurodevelopmental disorders. Using trio exome sequencing, we identified rare bi-allelic pathogenic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. The DOHH variants are associated with a neurodevelopmental phenotype that is similar to phenotypes caused by DHPS or EIF5A variants and includes global developmental delay, intellectual disability, facial dysmorphism, and microcephaly. A two-dimensional gel analyses revealed the accumulation of deoxyhypusine-containing eIF5A [eIF5A(Dhp)] and a reduction in the hypusinated eIF5A in fibroblasts derived from affected individuals, providing biochemical evidence for deficiency of DOHH activity in cells carrying the bi-allelic DOHH variants. Our data suggest that rare bi-allelic variants in DOHH result in reduced enzyme activity, limit the hypusination of eIF5A, and thereby lead to a neurodevelopmental disorder. This article describes mutations in DOHH as a cause of intellectual disability. These mutations decrease the activity of the eIF5A protein, whose dysfunction is known to cause intellectual disability. [ABSTRACT FROM AUTHOR]

DYRK1A haploinsufficiency syndrome is a well‐established neurodevelopmental disorder, but detailed information on the range of cognitive and behavioral issues associated with the condition is limited. We studied 24 participants with likely pathogenic or pathogenic variants in DYRK1A through the Simons Searchlight study and systematically assessed their medical history and development using standardized instruments: Vineland Adaptive Behavior Scale II (VABS‐II) and Child Behavior Checklists/1.5‐5 and 6‐18 (CBCL/1.5‐5, CBCL/6‐18). All of the individuals in the cohort had neurological manifestations including intellectual disability or developmental delay, microcephaly, autism spectrum disorder, and/or seizures. The severity of the neurodevelopmental disorder was variable with a few children scoring in the moderately low range on the adaptive behavior composite score on the VABS‐II. This study confirms the association of DYRK1A haploinsufficiency with neurodevelopmental disabilities, microcephaly, autism spectrum disorder, and epilepsy and quantifies the range of adaptive behaviors. [ABSTRACT FROM AUTHOR]

Background Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. Methods Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder. Results We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p. (Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. Conclusion We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management. [ABSTRACT FROM AUTHOR]

Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders. Pseudouridine synthase‐3 encoded by PUS3 is an enzyme important for modification of various RNAs, including transfer RNA (tRNA). Here we present the clinical and genetic features of 21 individuals with biallelic PUS3 variants: seven new and 14 previously reported individuals, where clinical features of two were updated. The clinical and genetic information were collected through collaborations or by literature search. All individuals were characterized by the local clinicians and the gene variants were identified by next generation sequencing (NGS) based methodologies. The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly. Gray sclera, which has previously been suggested to be a characteristic feature of PUS3‐associated phenotypes, was reported in only seven individuals. The patients had some dysmorphic facial features, but a recognizable gestalt was not observed. In conclusion, homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder. Further functional studies are necessary to understand involvement of PUS3 and tRNA biogenesis in normal and abnormal brain development. [ABSTRACT FROM AUTHOR]

Objective To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. Methods Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. Results LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. Conclusion These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene. [ABSTRACT FROM AUTHOR]

Desbuquois dysplasia is a very severe and sometimes lethal form of osteochondrodysplasia characterized by prenatal onset of severe micromelic short stature, joint laxity with multiple joint dislocations, specific radiographic features, and facial dysmorphism. Here, we report a case for which whole exome sequencing allowed early prenatal diagnosis of Desbuquois dysplasia before the detection of characteristic ultrasound signs of the disease. [ABSTRACT FROM AUTHOR]

Dysregulated transforming growth factor TGF-β signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-β-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-β signaling, ipo8 −/− zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8 −/− zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-β signaling during development and reinforces the existing link between TGF-β signaling and connective tissue defects. [ABSTRACT FROM AUTHOR]

Intragenic rearrangements and sequence variants in the calmodulin-binding transcription activator 1 gene (CAMTA1) can result in a spectrum of clinical presentations, most notably congenital ataxia with or without intellectual disability. We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novel CAMTA1 sequence variant. Furthermore, by identifying an additional, recurrent CAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated with CAMTA1 gene mutations. [ABSTRACT FROM AUTHOR]

Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we performed genetic analysis using targeted NGS of 22 already known and candidate genes in a cohort of 1,102 affected individuals. The panel design, library preparation, and sequencing reactions were performed using the Ion AmpliSeq technology. Pathogenic variants were detected in 16 genes in 245 patients (22%), including 186 (17%) and 59 (5%) dominant and recessive cases, respectively. Results confirmed that OPA1 variants are responsible for the majority of dominant IONs, whereas ACO2 and WFS1 variants are also frequently involved in both dominant and recessive forms of ION. All pathogenic variants were found in genes encoding proteins involved in the mitochondrial function, highlighting the importance of mitochondria in the survival of retinal ganglion cells. [ABSTRACT FROM AUTHOR]

The family of Tre2‐Bub2‐Cdc16 (TBC)‐domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP‐independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss‐of‐function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B‐deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival. [ABSTRACT FROM AUTHOR]

RING Finger Protein 113 A (RNF113A, MIM 300951) is a highly conserved gene located on chromosome Xq24‐q25, encoding a protein containing two conserved zinc finger domains involved in DNA alkylation repair and premessenger RNA splicing. To date, only one pathogenic variant of RNF113A, namely c.901C>T; p.Gln301Ter, has been reported in humans by Tarpey et al. in 2009. Thereafter, Corbett et al. stated that this variant was responsible for an X‐linked form of nonphotosensitive trichothiodystrophy associated with profound intellectual disability, microcephaly, partial corpus callosum agenesis, microphallus, and absent or rudimentary testes. This variant was then shown to alter DNA alkylation repair, providing an additional argument supporting its pathogenicity and important clues about the underlying pathophysiology of nonphotosensitive trichothiodystrophy. Using exome sequencing, we identified exactly the same RNF113A variant in two fetuses affected with abnormalities similar to those previously reported by Corbett et al. To our knowledge, this is the second report of a RNF113A pathogenic variant in humans. [ABSTRACT FROM AUTHOR]

Gain-of-function variants in the KDF1 gene cause hidradenitis suppurativa associated with ectodermal dysplasia by stabilizing I B kinase I KDF1 i has previously been identified as a causative gene for hypohidrotic ectodermal dysplasia (ED) associated with hidradenitis suppurativa (HS) of variable severity in a large family carrying a heterozygous missense variant (c.753C > A p.Phe251Leu) in the I KDF1 i gene,[1] which was identified using positional mapping and exome sequencing. Moreover, both patient 1 and 2 exhibited high transcription rates of interferon (IFN)-stimulated genes (ISGs) including I IFIT1 i , I IFI27 i , I IFI44L i , I ISG15 i , I RSAD2 i and I SIGLEC1 i , which was indicative of ongoing type I IFN responses (Figure 1b). [Extracted from the article]

TTI2 (MIM 614126) has been described as responsible for autosomal recessive intellectual disability (ID; MRT39, MIM:615541) in only two inbred families. Here, we give an account of two individuals from two unrelated outbred families harbouring compound heterozygous TTI2 pathogenic variants. Together with severe ID, progressive microcephaly, scoliosis and sleeping disorder are the most striking features in the two individuals concerned. TTI2, together with TTI1 and TELO2, encode proteins that constitute the triple T heterotrimeric complex. This TTT complex interacts with the HSP90 and R2TP to form a super‐complex that has a chaperone function stabilising and maturing a number of kinases, such as ataxia‐telangiectasia mutated and mechanistic target of rapamycin, which are key regulators of cell proliferation and genome maintenance. Pathogenic variants in TTI2 logically result in a phenotype close to that caused by TELO2 variants. [ABSTRACT FROM AUTHOR]

GLO:8DU/01apr21:cge13902-toc-0001.jpg PHOTO (COLOR): . gl Biallelic mutations in I TPO i are responsible for thyroid dyshormonogenesis type 2A (TDH2A, MIM: 274500), an autosomal recessive disorder. Moreover, the sensorineural deafness in PDS is generally congenital or pre-lingual, severe to profound, with possible sudden worsening and is occasionally associated with vestibular syndrome, whereas in I TPO i -related deafness, hearing loss is mild to moderate. [Extracted from the article]

Perrault syndrome (PS) is characterized by the association of sensorineural hearing loss and gonadic dysgenesis. The disease frequency is not well known as PS is frequently underdiagnosed. PS diagnosis may be difficult to reach according to the high phenotypic and genotypic heterogeneity. The deafness was classically described as bilateral, mild to profound but may also be progressive and even unilateral. Gonadal dysgenesis was mainly described in female. This dysgenesis seems to be constant with a wide range of severity. Neurological features (cerebellar ataxia, polyneuropathy, intellectual disability) may be associated. Autosomal recessive mutations in 5 different genes (TWNK, CLPP, HARS2, LARS2 and HSD17B4) have been identified in PS. Four of them (TWNK, CLPP, HARS2, LARS2) are implicated in mitochondrial metabolism. HSD17B4 is involved in peroxysomial metabolism. [ABSTRACT FROM AUTHOR]

The pLI score reflects the tolerance of a given gene to the loss of function on the basis of the number of protein truncating variants, that is, the frameshift, splice donor, splice acceptor, and stop‐gain variants referenced for this gene in control databases weighted by the size of the gene and the sequencing coverage. It is frequently used to prioritize candidate genes when analyzing whole exome or whole genome data. We list here the main pitfalls to consider before using this score. Concrete illustrations are given for each of these pitfalls. [ABSTRACT FROM AUTHOR]

Congenital heart disease affects around 1% of live births worldwide and can be associated with a wide range of neurodevelopmental disorders. Genetic factors are a major risk factor for poorer neurodevelopmental outcomes. Recent studies have highlighted the complexity of the underlying genetic contributions, including monogenic, oligogenic, and polygenic factors, and their interrelatedness with other risk factors such as preoperative factors (preterm birth, extracardiac malformation, and low birth weight), perioperative factors (anesthesia, type of surgery use of extracorporeal membrane oxygenation, cyanosis, and length of stay in the intensive care unit), postoperative factors (function of the heart after the surgery), and psychosocial factors (socioeconomic status or parent education). [ABSTRACT FROM AUTHOR]

Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans , knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation. [ABSTRACT FROM AUTHOR]