Impaired Intellectual Development Research Articles

Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases.

P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We determined the expression, localization and ATPase activity of four variants of ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar ataxia, impaired intellectual development and disequilibrium syndrome 4 (CAMRQ4). Two variants, G447R and A772P, harboring mutations in catalytic domains, expressed at low levels and mislocalized in cells. In contrast, the E459Q variant in a flexible loop displayed wild-type expression levels, Golgi-endosome localization and ATPase activity. The R1147W variant expressed at 50% of wild-type levels but showed normal localization and activity. These results indicate that the G447R and A772P mutations cause CAMRQ4 through protein misfolding. The E459Q mutation is unlikely to be causative, whereas the R1147W may display a milder disease phenotype. Using various programs that predict protein stability, we show that there is a good correlation between the experimental expression of the variants and in silico stability assessments, suggesting that such analysis is useful in identifying protein misfolding disease-associated variants.

Intellectual Development Diagnostics in Athletes with Intellectual and Physical Disabilities

In the article the diagnostic so intellectual development in athletes with intellectual and physical disabilities discussed. Any child from the age of 8 and any person with intellectual disabilities can train and participate in Special Olympics competitions. It has been determined that this must meet the criteria for delayed or impaired intellectual development based on the standard indicator - the IQ score, other indicators, medical examination report and doctor’s permission. The purpose of the article is to substantiate the methodology for diagnosing athletes with intellectual and physical disabilities that adhere to existing international rules for specific sports. To effectively implement the classification in the competitive process of paralympians, human factor influence on classification results should be minimized. One of the key figures in the classification process is the classifier. This classifier allows assessing the level of preserve debilities of athletes and determines the outcome of athletes’ classification. This imposes strict requirements both on the moral qualities of the classifier and on his her level of professionals kill. The diagnostics of intellectual development is carried out according to the criteria established by the World Health Organization, the International Classification of Diseases, using the Wechsler Intelligence Scale methodology (WAIS, WISC). The level of social adaptation and adaptive behavior disorders are determined by a special set of socially significant indicators. They are defined in specially designed questionnaire forms A, B, C. The internationally recognized Vineland Adaptive Behavior Scale (VABS) is also used. The total quantitative data from forms A, B, C to determine the overall level of adaptive behavior is or dersisused and calculated as the arithmetic mean.

Prenatal diagnosis of PIGV-related hyperphosphatasia with impaired intellectual development (HPMRS) through next generation sequencing

Prenatal diagnosis of PIGV-related hyperphosphatasia with impaired intellectual development (HPMRS) through next generation sequencing

Пиктограммы как метод невербальной коммуникации для подростков с нарушением интеллектуального развития

The article deals with the main features of communication of children and adolescents with impaired intellec-tual development. A comparative study of the nonverbal alternative communication perception was conducted with the participation of adolescents with impaired intellectual development (N = 92) and with normal intelli-gence (N = 92). Participants were asked to perform a pictograph translation task in a verbal context. The results of the study of pictogram perception in a verbal context indicate passive thinking and impaired cognitive com-ponent of thinking in persons with impaired intellectual development. The analysis of oculomotor activity during pictogram perception suggests a shorter duration of the lexical processing activation. Conclusion dwells upon the fact that the effectiveness of nonverbal graphic means of communication for persons with impaired intel-lectual development is twofold: nonverbal means of communication are able to expand the communicative abilities of this group, but it is necessary to take into account their cognitive characteristics when using methods of graphic alternative communication.

Intragenic homozygous duplication in HEPACAM is associated with megalencephalic leukoencephalopathy with subcortical cysts type 2A.

Disease-causing variants in HEPACAM are associated with megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A, MIM# 613,925, autosomal recessive), and megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development (MLC2B, MIM# 613,926, autosomal dominant). These disorders are characterised by macrocephaly, seizures, motor delay, cognitive impairment, ataxia, and spasticity. Brain magnetic resonance imaging (MRI) in these individuals shows swollen cerebral hemispheric white matter and subcortical cysts, mainly in the frontal and temporal regions. To date, 45 individuals from 39 families are reported with biallelic and heterozygous variants in HEPACAM, causing MLC2A and MLC2B, respectively. A 9-year-old male presented with developmental delay, gait abnormalities, seizures, macrocephaly, dysarthria, spasticity, and hyperreflexia. MRI revealed subcortical cysts with diffuse cerebral white matter involvement. Whole-exome sequencing (WES) in the proband did not reveal any clinically relevant single nucleotide variants. However, copy number variation analysis from the WES data of the proband revealed a copy number of 4 for exons 3 and 4 of HEPACAM. Validation and segregation were done by quantitative PCR which confirmed the homozygous duplication of these exons in the proband and carrier status in both parents. To the best of our knowledge, this is the first report of an intragenic duplication in HEPACAM causing MLC2A.

Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)

Glycosylphosphatidylinositols (GPIs) anchor over 150 proteins as GPI-anchored proteins (GPI-APs) with crucial roles in diverse biological processes. The highly conserved biosynthesis of GPI-APs involves precise steps with at least 21 genes, categorized as PIG and PGAP genes. Pathogenic variants in these genes are linked to human diseases, highlighting the importance of each biosynthesis step. PGAP2 stands out among these genes due to its association with an expanded clinical spectrum of neurodevelopmental disorder (NDD) phenotypes with biallelic pathogenic variants. We present four patients from two families, one consanguineous and the other nonconsanguineous, each displaying distinct clinical presentations, including intellectual disability, hyperphosphatasia, hearing impairment, and epilepsy, as well as craniofacial and digital anomalies. Genetic analyses revealed homozygous and novel compound heterozygous missense variants in PGAP2 in four affected individuals, confirming the molecular diagnosis of hyperphosphatasia with impaired intellectual development syndrome 3 (HPMRS3). Importantly, the three amino acids affected by missense variants exhibit complete conservation in 10 vertebrate species, illuminating their crucial role in the gene’s functionality. Protein modeling provided additional evidence for the pathogenicity of the three substitutions, demonstrating their detrimental impact on protein folding and putative protein-protein interactions, ultimately leading to impaired protein function. The four patients in our study displayed common phenotypic features, such as brachydactyly, camptodactyly, and syndactyly, which have not been previously documented in individuals with PGAP2 variants. Notably, the occurrence of macrocephaly in two affected brothers from a consanguineous Pakistani family represents a novel finding. These previously unreported digital anomalies, along with macrocephaly and the identification of novel compound heterozygous variants, contribute to the expansion of the phenotypic and genotypic spectrum of HPMRS3 associated with PGAP2 variants.

The Outcome of the Treatment of Malnourished Children Treated by Ready To Use Therapeutic Food and Ready to Use Supplementary Food in Wad ElBashir Heath Cente 2021

introduction: Malnutrition includes both undernutrition and overnutrition. Child undernutrition is a major global health problem that is more common in low-income countries like Sudan, it can cause childhood morbidity, mortality, and impaired intellectual development. Objective: This study was conducted to assess the outcome of malnourished children treated with ready to-Use Therapeutic Food (RUTF), and ready to-Use Supplementary Food (RUSF) in Wad Elbasheir Health Centre in Ombada Locality Methods: This is an analytical Cross-Sectional facility-based Study conducted at Wad Elbasheir Health Centre. A convenient nonprobability sampling technique was used in this study. Data were collected using a datasheet after being pretested. Data were collected from secondary data from the records of malnourished children treated by the RTUF and RUSF. Results: The majority of the participants of this study were aged between 6 to 23 months (84%) and most of the participants were females (56%). This study showed that 70 (24%) of the participants were classified as severe Acute Malnutrition (SAM), while 218 (76%) were classified as moderate Acute malnutrition (MAM). This study showed that having a smaller number of children in the family and middle Upper Arm Circumference (MUAC) between 11.5-12.5 cm were more associated with recovery. Moreover, this study showed that children who use amoxicillin or anti-worms were more likely to be recovered from malnutrition. Conclusion: RUTF was designed for the nutritional management of children with uncomplicated acute malnutrition treated as outpatients. In this study, most of the children recovered. In addition, this study found that several factors were associated with better outcomes including fewer children in the family, MUAC between 11.5-12.5 cm, having MAM (compared to having SAM), and using amoxicillin or anti-worms.

Identification of novel and de novo GABRB1 mutation in Chinese patient with developmental and epileptic encephalopathy 45.

Developmental and epileptic encephalopathy 45 (DEE45) is an autosomal dominant disease caused by variation in the gamma-aminobutyric acid type A receptor subunit beta 1 (GABRB1) gene. Affected individuals have severely impaired intellectual development, hypotonia, and other persistent neurological deficits. However, DEE45 is rare; only four infants with DEE45 have been reported worldwide and no case has been reported in China. Confirming a diagnosis of DEE45 is of great significance for guiding further treatment, assessing patient prognosis, and genetic counseling. The clinical characteristics of DEE45 and the medical history of DEE45 patients requires supplementation and clarification. Here, we present the clinical and genetic findings of a 7-year-old girl with DEE45 carrying a novel de novo GABRB1 mutation (c.858_859delinsTT, p.286_287delinsIleSer) identified by whole exome sequencing (WES). The mutation is phylogenetic conserved in the second helix of the β1-subunit's transmembrane region. Western blot and RT-qPCR both indicated significant increase in the expression levels of GABRB1 mutant when compared with wild. The proband has epileptic encephalopathy and experienced refractory epilepsy onset at age 2 months and showed developmental delay at age 8 months. Electroencephalography (EEG) displayed hypsarrhythmia. Magnetic resonance imaging (MRI) showed no significant abnormalities in the internal structure of the patient's brain, which is displayed in two previously reported cases. The patient's symptoms of hypotonia, ataxia, profound mental retardation, and dysmetria became evident with development. In summary, we report the genetic and clinical characteristics of the first Chinese patient with DEE45 and explores the relationship between mutation and clinical symptoms.

THE SYSTEM OF CORRECTIVE AND DEVELOPMENTAL EDUCATION OF MATHEMATICS FOR PRIMARY SCHOOL STUDENTS WITH INTELLECTUAL DEVELOPMENT DISABILITIES

The article discloses the problem of corrective and developmental mathematics education for primary school students with impaired intellectual development. It has been established that in the psychological and pedagogical literature there are quite a lot of studies devoted to the problem of failure of elementary school students. It was revealed that inclusive remedial and developmental education classes are one of the effective forms of differentiated education, which allows students with intellectual disabilities to learn the main school curriculum and creates favorable opportunities for their development. The current state of mathematics teaching methods in inclusive classes of remedial and developmental education is analyzed. It has been proven that special educational conditions must be created to learn mathematics. The methodical recommendations for conducting lessons and studying individual sections and topics are analyzed, the peculiarities of using methods and techniques are indicated. It was established that most of the recommendations are aimed only at children with mentalretardation, which are not always effective for all students in remedial and developmental classes.A system of corrective and developmental work in mathematics with students of elementary school of corrective and developmental education has been developed, which takes into account the state of knowledge, peculiarities of learning the material by students and strengthens the corrective and developmental potential of mathematics, which includes: changing the structure of the content of educational material (the presence of preparatory stages aimed at forming prerequisites for the successful learning of mathematics; a change in the sequence of learning due to the joint and simultaneous study of family sections and topics, as well as reciprocal actions); methods of consolidation of didactic units, presentation of information in a visual form, methods of comparison, generalization, induction, analogies; authorʼs complexes of corrective and developmental exercises on mathematical material, which allow solving educational, developmental and corrective tasks, which allows to increase the quality of knowledge and contributes to the improvement of studentsʼ cognitive activity. General recommendations for teaching mathematics in inclusive remedial and developmental classes for students with intellectual disabilities have been formulated. We see prospects for further research in the disclosure of teachersʼ readiness for activities aimed at primary school studentsʼ mastery of educational material in mathematics in inclusive classes of remedial and developmental education.
 Keywords: inclusive classes; remedial and developmental education; mathematics; elementary school students; academic failure; cognitive processes; mental activity; intellectual development disorders.

OR17-02 Combining Transcriptomics And Proteomics To Unveil Possible PROP1 Interactors During Embryonic Pituitary Development

Abstract Disclosure: L. Iglesias Garcia: None. M.F. Mercogliano: None. C. Schuster: None. L. Cheung: None. S.A. Camper: None. M. Marti: None. M.I. Perez-Millan: None. Congenital hypopituitarism (CH) is a deficiency of one or more hormones produced by the anterior pituitary. The most frequently mutated gene in CH is PROP1, which has a very dynamic expression pattern. In Prop1 mutant mice, the pituitary is dysmorphic, with increased apoptosis and abnormal vascularization. These mutant mice are dwarfs and develop hypopituitarism. In previous work we have shown that PROP1 has a key role in stimulating progenitors to undergo an EMT-like transition before differentiation. The general objective of this work was to elucidate the PROP1 protein complexes in order to understand its role during pituitary development and to evaluate them as candidate genes that can cause congenital hypopituitarism. A GHFT-1 murine cell line expressing biotinylated Prop1 was used and co-immunoprecipitation (Co-IP) assays were performed, followed by Rapid Immunoprecipitation Mass spectrometry of Endogenous (RIME). We obtained an initial set of 786 proteins that co precipitate with PROP1. Ontology enrichment analysis shows that PROP1 immunoprecipitated with several nuclear proteins related to transcriptional regulation and splicing and also with many non nuclear proteins related to cell adhesion and migration. We used LISA and TRANSFAC to predict transcriptional regulators using as input the genes that intersected from Prop1-ChIP-Seq and RNA-seq experiments and obtained 536 genes. We compared this result with the potential PROP1 interaction proteins derived from the RIME to obtain a final list of 37 transcription factors. One possible candidate from this list is the Nuclear Factor I/B or NFIB. Mutations in this gene are related to macrocephaly with impaired intellectual development. We performed a scRNA-Seq at P4 and it showed that NFIB expresses in the same cell clusters as Prop1. Also, we have preliminary results indicating that the pituitary in NFIB KO mice at E13.5 is dysmorphic. Further experimental work is needed to validate Prop1 interaction partners and to have a better understanding of Prop1 mechanism during pituitary development. Presentation: Saturday, June 17, 2023

Greater maltreatment severity is associated with smaller brain volume with implication for intellectual ability in young children

BackgroundChildhood maltreatment profoundly alters trajectories of brain development, promoting markedly increased long-term health risks and impaired intellectual development. However, the immediate impact of maltreatment on brain development in children and the extent to which altered global brain volume contributes to intellectual development in children with maltreatment experience is currently unknown. We here utilized MRI data obtained from children within 6 months after the exposure to maltreatment to assess the association of maltreatment severity with global brain volume changes. We further assessed the association between maltreatment severity and intellectual development and tested for the mediating effect of brain volume on this association. MethodWe used structural MRI (3T) in a sample of 49 children aged 3–5 years with maltreatment exposure, i.e. emotional and physical abuse and/or neglect within 6 months, to characterize intracranial and tissue-specific volumes. Maltreatment severity was coded using the Maternal Interview for the Classification of Maltreatment. IQ was tested at study entry and after one year using the Snijders Oomen Nonverbal Test. ResultsHigher maltreatment severity was significantly correlated with smaller intracranial volume (r = -.393, p = .008), which was mainly driven by lower total brain volume (r = -.393, p = .008), which in turn was primarily due to smaller gray matter volume (r = -.454, p = .002). Furthermore, smaller gray matter volume was associated with lower IQ at study entry (r = -.548, p < .001) and predicted IQ one year later (r = -.493, p = .004). The observed associations were independent of potential confounding variables, including height, socioeconomic status, age and sex. ImportanceWe provide evidence that greater maltreatment severity in early childhood is related to smaller brain size at a very young age with significant consequences for intellectual ability, likely setting a path for far-reaching long-term disadvantages. Insights into the molecular and neural processes that underlie the impact of maltreatment on brain structure and function are urgently needed to derive mechanism-driven targets for early intervention.

Orthodontic Management of Severe Hypodontia and Impacted Maxillary Second Molars in a Patient with Sotos Syndrome.

Sotos syndrome is a genetic disorder characterized by distinct craniofacial features, overgrowth in childhood, and impaired intellectual development. We herein report the successful orthodontic treatment of a 14-year-old boy with Sotos syndrome caused by a heterozygous mutation in the NSD1 gene. He showed severe hypodontia, impaction of the maxillary second molars and a skeletal Class III jaw-base relationship. Orthodontic management, including space control by protraction of the maxillary first molars and traction of the impacted molars, was performed using fixed appliances and miniscrews. As a result, acceptable occlusion was obtained without any discernible relapse 18 months postretention.

Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis.

Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.

Molecular and Functional Characterisation of a Novel Intragenic 12q24.21 Deletion Resulting in MED13L Haploinsufficiency Syndrome.

Background and Objectives: Heterozygous pathogenic variants in the MED13L gene cause impaired intellectual development and distinctive facial features with or without cardiac defects (MIM #616789). This complex neurodevelopmental disorder is characterised by various phenotypic features, including plagiocephaly, strabismus, clubfoot, poor speech, and developmental delay. The aim of this study was to evaluate the clinical significance and consequences of a novel heterozygous intragenic MED13L deletion in a proband with clinical features of a MED13L-related disorder through extensive clinical, molecular, and functional characterisation. Materials and Methods: Combined comparative genomic hybridisation and single-nucleotide polymorphism array (SNP-CGH) was used to identify the changes in the proband's gDNA sequence (DECIPHER #430183). Intragenic MED13L deletion was specified via quantitative polymerase chain reaction (qPCR) and Sanger sequencing of the proband's cDNA sample. Western blot and bioinformatics analyses were used to investigate the consequences of this copy number variant (CNV) at the protein level. CRISPR-Cas9 technology was used for a MED13L-gene-silencing experiment in a culture of the control individual's skin fibroblasts. After the MED13L-gene-editing experiment, subsequent functional fibroblast culture analyses were performed. Results: The analysis of the proband's cDNA sample allowed for specifying the regions of the breakpoints and identifying the heterozygous deletion that spanned exons 3 to 10 of MED13L, which has not been reported previously. In silico, the deletion was predicted to result in a truncated protein NP_056150.1:p.(Val104Glyfs*5), partly altering the Med13_N domain and losing the MedPIWI and Med13_C domains. After MED13L gene editing was performed, reduced cell viability; an accelerated aging process; and inhibition of the RB1, E2F1, and CCNC gene expression were found to exist. Conclusions: Based on these findings, heterozygous intragenic 12q24.21 deletion in the affected individual resulted in MED13L haploinsufficiency due to the premature termination of protein translation, therefore leading to MED13L haploinsufficiency syndrome.

A novel homozygous synonymous splicing variant in SELENOI gene causes Spastic Paraplegia 81.

Hereditary spastic paraplegia-81 is a recently identified, rare autosomal recessive disease, caused due to biallelic pathogenic variants in the SELENOI gene, with only two families reported to date. The features documented in the two previous affected families include sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities, and cerebral and cerebellar atrophy. In the present study, we performed exome sequencing analysis in a single-family with two affected siblings to identify the genetic cause of complicated hereditary spastic paraplegia. The results were further confirmed by Sanger sequencing, cDNA analysis and 3D protein modelling. Exome sequencing identified a homozygous, synonymous variant in the SELENOI gene (NM_033505.4:c.126G>A:p.(Lys42Lys) in both the siblings. Sanger sequencing confirmed the heterozygous status in both parents consistent with the autosomal recessive inheritance. This variant has been found to disrupt normal splicing and is likely to lead to skipping of exon 2, causing in-frame deletion of SELENOI N-terminal 23 amino acids[NM_033505.4:c.57_126del:p.(Tyr20_Lys42del)] further leading to the structural changes in the protein. We report a novel homozygous synonymous variant in the SELENOI gene causing abnormal splicing in two patients affected with Hereditary spastic paraplegia-81. This report further expands the phenotypic and genotypic spectrum of Hereditary spastic paraplegia-81.

Diagnostic yield of chromosomal microarray and trio whole exome sequencing in congenital brain anomalies

IntroductionThe deductive method: from karyotyping to aCGH and WES is an important aspect in the diagnosis and search for the causes of intellectual disability due to congenital brain anomalies. There is recommendation to exclude the presence of CNV or monogenic variants for patients with a normal karyotype, but with a clinical picture of syndromic disease.ObjectivesImprovement of diagnosis of intellectual disability.MethodsaCGH with 60K Agilent microarrays, WES with SureSelect Human All Exon V8ResultsPathogenic or potentially pathogenic CNVs were excluded previously by aCGH for 10 families (total 32 people, 2 families had 2 children) with intellectual disability and congenital brain anomalies (for example, polymicrogyria, pachygyria, lissencephaly). The WES identified candidate variants for all families that can lead to impaired neurodevelopment, including 3 pathogenic variants in 3 families, 3 likely pathogenic in three other families, and 10 variants with uncertain clinical significance for 4 families. Almost all of these variants were identified de novo, except for one family, where the proband has been a compound heterozygous for two variants in the RELN gene. The first case of pathogenic mutation de novo was detected in a girl with agenesis of the corpus callosum. It was a missense mutation DYNC1H1 (NM_001376.5): c.4868G&gt;A (p.Arg1623Gln), which leads to impaired intellectual development in autosomal dominant type 13 (OMIM 614563). The second variant was detected in a boy with corpus callosum agenesis, pontine hypogenesis, pachygyria in the frontal lobes. It was a missense variant MACF1 (ENST00000567887.5): c.21989A&gt;G(p.Asp7330Gly), which leads to lissencephaly 9 with complex brainstem malformation (OMIM 614563). The third variant was found in a girl with epilepsy and impaired myelination of the white matter of the parietal-occipital areas of the cerebral hemispheres. It was a missense variant CDKL5 (NM_001323289.2):c.404-1G&gt;A that leads to developmental and epileptic encephalopathy 2 (OMIM 300672).ConclusionsSixteen candidate variants potentially responsible for mental health were reported in this study. Most of these variants were missense changes in genes. All except one anomalies arisen de novo. Trio-based WES has been shown to be an important step in making a genetic diagnosis if other chromosomal and subchromosomal abnormalities had been excluded. The clinical description of the patient is the most important step for the correct interpretation of WES results, which allows to establish the exact genetic cause of the disease if several variants with unclear clinical significance were previously identified.This study was supported by the Russian Science Foundation, grant 21-65-00017, https://rscf.ru/project/21-65-00017/Disclosure of InterestNone Declared

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 in two new patients with the same homozygous TMCO1 variant and review of the literature

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1; OMIM#213980) is a rare autosomal recessive disorder characterized by the clinical triad of developmental delay and/or intellectual disability, a typical facial gestalt with brachycephaly, highly-arched bushy eyebrows, synophrys, hypertelorism, wide nasal bridge, and short nose, as well as multiple vertebrae and rib malformations, such as bifid and fused ribs and abnormal vertebral segmentation and fusion. Biallelic loss-of-function variants in TMCO1 cause CFSMR1. We report on two unrelated Egyptian patients with a phenotype suggestive of CFSMR. Single whole-exome sequencing in patient 1 and Sanger sequencing of TMCO1 in patient 2 revealed the same homozygous TMCO1 nonsense variant c.187C > T/p.(Arg63*) in both affected individuals; patients’ healthy parents were heterozygous carriers of the variant. Congenital hearing loss in patients 1 and 2 is an occasional finding in individuals affected by CFSMR. Camptodactyly and syndactyly, which were noted in patient 2, have not or rarely been reported in CFSMR. Review of the literature revealed a total of 30 individuals with the clinically recognizable and unique phenotype of CFSMR1, including the patients reported here, who all carried biallelic TMCO1 variants. Six different TMCO1 variants have been reported in the 30 patients from 14 families, comprising three nonsense, two 2-bp deletions, and a splice donor site variant. All disease-associated TMCO1 variants likely represent null alleles resulting in absence of the encoded protein. TMCO1 has been proposed to act as a Ca2+ channel, while other data revealed TMCO1 as a mitochondrial protein and a component of the translocon at the endoplasmic reticulum, a cellular machinery important for the biogenesis of multi-pass membrane proteins. RAB5IF/C20orf24 has recently been identified as causative gene for craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2; OMIM#616994). Heterodimerization of RAB5IF/C20orf24 and TMCO1 and their interdependence may suggest a pathophysiological role of ER-mitochondria interaction underlying CFSMR.

Haploinsufficiency as a Foreground Pathomechanism of Poirer-Bienvenu Syndrome and Novel Insights Underlying the Phenotypic Continuum of CSNK2B-Associated Disorders.

CSNK2B encodes for the regulatory subunit of the casein kinase II, a serine/threonine kinase that is highly expressed in the brain and implicated in development, neuritogenesis, synaptic transmission and plasticity. De novo variants in this gene have been identified as the cause of the Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) characterized by seizures and variably impaired intellectual development. More than sixty mutations have been described so far. However, data clarifying their functional impact and the possible pathomechanism are still scarce. Recently, a subset of CSNK2B missense variants affecting the Asp32 in the KEN box-like domain were proposed as the cause of a new intellectual disability-craniodigital syndrome (IDCS). In this study, we combined predictive functional and structural analysis and in vitro experiments to investigate the effect of two CSNK2B mutations, p.Leu39Arg and p.Met132LeufsTer110, identified by WES in two children with POBINDS. Our data prove that loss of the CK2beta protein, due to the instability of mutant CSNK2B mRNA and protein, resulting in a reduced amount of CK2 complex and affecting its kinase activity, may underlie the POBINDS phenotype. In addition, the deep reverse phenotyping of the patient carrying p.Leu39Arg, with an analysis of the available literature for individuals with either POBINDS or IDCS and a mutation in the KEN box-like motif, might suggest the existence of a continuous spectrum of CSNK2B-associated phenotypes rather than a sharp distinction between them.

Uncovering the genetic basis of hyperphosphatasia with impaired intellectual development syndrome type 2: identification of a novel biallelic nonsense mutation in PIGO gene

Background: Glycosylphosphatidylinositol (GPI) is a glycolipid containing phosphatidylinositol related to the protein surfaces by covalent attachment. Inherited GPI deficiencies have various phenotypic chrematistics, which range from intellectual disability to dysmorphic features, epilepsy, and other severe anomalies. Methods: Molecular diagnosis was performed using whole exome sequencing (WES) followed by Sanger sequencing. Results: WES revealed a novel homozygous nonsense variant (c.250C&amp;gt;T; p.Gln84Ter) in the exon 2 of the phosphatidylinositol glycan anchor biosynthesis class Ogene that might explain the disease phenotype in the patient. Conclusion: This study will help in proper genetic counselling of the family and help in genotype-phenotype correlation in the future.

Hao-Fountain syndrome and genital disorders: report of a new possible association

BackgroundHao-Fountain syndrome is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay and, in some males patients, it has been reported an association with hypogonadism. At present less than 50 cases are reported in literature.Case presentationWe report a case of this rare syndrome in a young female with isolated tubal torsion; our patients had different hospitalizations without treatment but during the last episode we decide to perform an abdominal surgical explortion. This is the first case in Literature with a new USP7 mutation.ConclusionsThis case opens new perspective in this rare syndrome and a review approach to isolated tubal torsion. These symptoms should be always well checked.