De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two ...independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.
Until recently, the cause of intellectual disability (ID) remained unexplained in at least 50% of affected individuals. Recent advances in genetic technologies led to great new opportunities to ...elucidate genetic defects implicated in ID. The introduction of genome‐wide technologies that are able to detect small chromosomal copy number variations led to the identification of several microdeletion/duplication syndromes and to the subsequent identification of single causative genes. By the recent implementation of whole exome sequencing (WES) in research and diagnostics, with the potential to identify disease causing variants throughout the human exome at the base‐pair level, a new revolution has started. Several studies showed that WES is effective in the identification of ID genes. Here we provide an historical overview of the advances in diagnostics of ID and illustrate the high diagnostic potential of current technologies by presenting the diagnostic survey that we performed in a series of 253 individuals with previously unexplained ID. This is the first study that systematically evaluated the diagnostic yield of the currently available and rapidly developing genetic diagnostic arsenal. The results of our study indicate that application of present‐day genetic diagnostic technologies lead to a significant increase in the number of patients that can be diagnosed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
De novo missense mutations and in‐frame coding deletions in the X‐linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de ...Lange syndrome in both males and females. For a long time, loss‐of‐function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy.
Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion c.2364del, p.(Asn788Lysfs*10), predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out‐of‐frame mRNA splice product p.(Leu808Argfs*6). By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy‐resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity – distinct from CdLS – and caused by de novo SMC1A LoF mutations.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The use of whole exome sequencing (WES) for diagnostics of children with rare genetic diseases raises questions about best practices in genetic counselling. While a lot of attention is now given to ...pre-test counselling procedures for WES, little is known about how parents experience the (positive, negative, or inconclusive) WES results in daily life. To fill this knowledge gap, data were gathered through in-depth interviews with parents of 15 children who underwent WES analysis. WES test results, like results from other genetic tests, evoked relief as well as worries, irrespective of the type of result. Advantages of obtaining a conclusive diagnosis included becoming more accepting towards the situation, being enabled to attune care to the needs of the child, and better coping with feelings of guilt. Disadvantages experienced included a loss of hope for recovery, and a loss by parents of their social network of peers and the effort necessary to re-establish that social network. While parents with conclusive diagnoses were able to re-establish a peer community with the help of social media, parents receiving a possible diagnosis experienced hurdles in seeking peer support, as peers still needed to be identified. These types of psychosocial effects of WES test results for parents are important to take into account for the development of successful genetic counselling strategies.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic ...review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects:
MSX1
,
PAX9
,
IRF6
,
TP63, KMT2D
,
KDM6A
,
SATB2
,
TBX22
,
TGFα
,
TGFβ3
,
TGFβR1
,
TGFβR2
,
FGF8
,
FGFR1
,
KISS1R
,
WNT3
,
WNT5A
,
CDH1
,
CHD7
,
AXIN2
,
TWIST1
,
BCOR
,
OFD1
,
PTCH1
,
PITX2
, and
PVRL1
. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the
GOTermMapper
(Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological ...processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the
thyroid hormone receptor interactor 12
(
TRIP12
) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features,
TRIP12
mutation carriers showed intellectual disability (ID). More recently,
TRIP12
was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private
TRIP12
mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the
TRIP12
gene and clinically review four previously published cases. The
TRIP12
mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability intelligence quotient (IQ) 76 in one individual, ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11
TRIP12
mutation-positive individuals and thereby expand the clinical spectrum of the
TRIP12
gene in non-syndromic intellectual disability with or without ASD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Kabuki syndrome (KS) is a Mendelian disorder, characterised by short stature, facial dysmorphisms and developmental delay and/or intellectual disability. Clarification of the ...neurocognitive profile in KS may provide directions for education and treatment interventions for KS. Previous studies on cognitive functioning in KS are scarce and have mainly focused on the general level of intelligence. The few more extensive studies suggested weaknesses in language skills, visuoconstruction, perceptual reasoning and speed of information processing. Other relevant domains such as memory, executive functioning and social cognition have not been studied yet.
Method
This is the first study in which cognitive functioning within multiple domains is systematically explored in 29 participants with KS (age range: 5–48 years) and compared to both norm groups (healthy population) and an appropriate control group of 15 individuals with other genetic syndromes (age range: 6–28 years).
Results
Compared to the norm groups of the cognitive test manuals, as expected, participants with KS show a weaker performance on all cognitive tests. Comparison with the more appropriate genetic control group indicates weaknesses in visuoconstruction and visual memory and no weaknesses in planning, cognitive flexibility or social cognition. Verbal memory seems to be a relative strength.
Conclusions
Individuals with KS suffer from specific weaknesses in visuoconstruction, in addition to their intellectual disability/developmental delay. These impairments in visuoconstruction plausibly result from problems in visual perceptual processing, which highlight the importance of the use of auditory cues instead of visual cues in targeted educational support and psychosocial interventions.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Okur‐Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable ...dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur‐Chung syndrome. To conclude, this is the second case series on Okur‐Chung syndrome, and an in‐depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.
Summary of all reported CSNK2A1 variations in Okur‐Chung neurodevelopmental syndrome. Most of the variations are located within the protein kinase domain of the gene, with position 198 being a mutation hotspot.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Phelan‐McDermid syndrome presents with specific deficits in neurocognition, cerebellar regulatory functioning and enhanced vulnerability for the development of atypical bipolar disorder.
...Phelan‐McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by a variable degree of intellectual disability, impaired speech and language as well as social communicative skills and mild dysmorphic features. The SHANK3 gene is thought to be a major contributor to the phenotype. Apart from the syndrome‐associated autistic features, symptoms from the bipolar spectrum can be discerned, in particular behavior instability and fluctuating mood culminating in a (hypo)manic state. In case of coincident major somatic events, a deteriorating course may occur. This study comprises seven adult patients (four females and three males; aged 21–44 years) with genetically proven PMS. Data from medical records were collected and extensive assessment of neuropsychological variables was performed to identify cognitive characteristics and their relation with psychopathology and treatment. All patients showed profound communication deficits and their developmental functioning ranged from 1.0 to 6.3 years. In addition, they had slow speed of information processing, impairment of attentional and executive functions and cognitive alexithymia. As to psychopathology, features from the affective and anxiety domains were prominent findings in these seven patients suggesting the presence of a bipolar spectrum disorder that could be effectively moderated with mood‐stabilizing agents. Results are discussed in terms of the putative involvement of structural brain abnormalities, in particular cerebellar vermis hypoplasia and corpus callosum thinning and their cognitive and emotional sequelae. It is concluded that the treatment of 22q13.3‐associated psychopathology should include prescription of mood‐stabilizing agents in combination with individually tailored contextual neuropsychological measures.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific ...X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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