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Journal of Medical Genetics Jan 2024The Aristaless-related homeobox () gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical... (Review)
Review
The Aristaless-related homeobox () gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of -related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants. In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited variants (n=33) or variants of unknown inheritance (n=20). Altogether, the clinical spectrum of females with heterozygous pathogenic variants is broad: 42.5% are asymptomatic, 16.4% have isolated agenesis of the corpus callosum (ACC) or mild symptoms (learning disabilities, autism spectrum disorder, drug-responsive epilepsy) without ID, whereas 41% present with a severe phenotype (ie, ID or developmental and epileptic encephalopathy (DEE)). The ID/DEE phenotype was significantly more prevalent in females carrying de novo variants (75%, n=15/20) versus in those carrying inherited variants (27.3%, n=9/33). ACC was observed in 66.7% (n=24/36) of females who underwent a brain MRI. By refining the clinical spectrum of females carrying pathogenic variants, we show that ID is a frequent sign in females with this X linked condition.
Topics: Male; Humans; Female; Genes, Homeobox; Homeodomain Proteins; Autism Spectrum Disorder; Mutation; Transcription Factors; Intellectual Disability; Phenotype; Agenesis of Corpus Callosum
PubMed: 37879892
DOI: 10.1136/jmg-2023-109203 -
Genes Jul 2023Intellectual disability (ID) is a prevalent neurodevelopmental disorder characterized by limitations in intellectual functioning and adaptive behavior. While the causes... (Review)
Review
Intellectual disability (ID) is a prevalent neurodevelopmental disorder characterized by limitations in intellectual functioning and adaptive behavior. While the causes of ID are still largely unknown, it is believed to result from a combination of environmental exposures and genetic abnormalities. Recent advancements in genomic studies and clinical genetic testing have identified numerous genes associated with neurodevelopmental disorders (NDDs), including ID. One such gene is , which plays a role in chromosome alignment and has been linked to a specific type of NDD called CHAMP1 disease. This report presents the case of a 21-year-old Lebanese female patient with a de novo mutation in . In addition to ID and NDD, the patient exhibited various clinical features such as impaired language, dysmorphic features, macrocephaly, thoracic hyperkyphosis, decreased pain sensation, and metabolic syndrome. These findings expand the understanding of the clinical spectrum associated with mutations and highlight the importance of comprehensive follow-up for improved prognosis. Overall, this case contributes to the knowledge of CHAMP1-related NDDs by describing additional clinical features associated with a mutation. The findings underscore the need for accurate diagnosis, thorough follow-up, and personalized care for individuals with mutations to optimize their prognosis.
Topics: Humans; Female; Young Adult; Adult; Follow-Up Studies; Intellectual Disability; Neurodevelopmental Disorders; Adaptation, Psychological; Cognition; Chromosomal Proteins, Non-Histone; Phosphoproteins
PubMed: 37628598
DOI: 10.3390/genes14081546 -
Epilepsia Open Dec 2023The aim of this study was to describe the epilepsy phenotype in a large international cohort of patients with KBG syndrome and to study a possible genotype-phenotype...
OBJECTIVE
The aim of this study was to describe the epilepsy phenotype in a large international cohort of patients with KBG syndrome and to study a possible genotype-phenotype correlation.
METHODS
We collected data on patients with ANKRD11 variants by contacting University Medical Centers in the Netherlands, an international network of collaborating clinicians, and study groups who previously published about KBG syndrome. All patients with a likely pathogenic or pathogenic ANKRD11 variant were included in our patient cohort and categorized into an "epilepsy group" or "non-epilepsy group". Additionally, we included previously reported patients with (likely) pathogenic ANKRD11 variants and epilepsy from the literature.
RESULTS
We included 75 patients with KBG syndrome of whom 26 had epilepsy. Those with epilepsy more often had moderate to severe intellectual disability (42.3% vs 9.1%, RR 4.6 [95% CI 1.7-13.1]). Seizure onset in patients with KBG syndrome occurred at a median age of 4 years (range 12 months - 20 years), and the majority had generalized onset seizures (57.7%) with tonic-clonic seizures being most common (23.1%). The epilepsy type was mostly classified as generalized (42.9%) or combined generalized and focal (42.9%), not fulfilling the criteria of an electroclinical syndrome diagnosis. Half of the epilepsy patients (50.0%) were seizure free on anti-seizure medication (ASM) for at least 1 year at the time of last assessment, but 26.9% of patients had drug-resistant epilepsy (failure of ≥2 ASM). No genotype-phenotype correlation could be identified for the presence of epilepsy or epilepsy characteristics.
SIGNIFICANCE
Epilepsy in KBG syndrome most often presents as a generalized or combined focal and generalized type. No distinctive epilepsy syndrome could be identified. Patients with KBG syndrome and epilepsy had a significantly poorer neurodevelopmental outcome compared with those without epilepsy. Clinicians should consider KBG syndrome as a causal etiology of epilepsy and be aware of the poorer neurodevelopmental outcome in individuals with epilepsy.
Topics: Humans; Infant; Abnormalities, Multiple; Intellectual Disability; Bone Diseases, Developmental; Tooth Abnormalities; Facies; Repressor Proteins; Epilepsy, Generalized; Transcription Factors
PubMed: 37501353
DOI: 10.1002/epi4.12799 -
Tijdschrift Voor Psychiatrie 2024Sexual behavior disorders in intellectual disability form several challenges, despite evolutions in treatment options and risk assessment. The use of antilibidinal... (Review)
Review
BACKGROUND
Sexual behavior disorders in intellectual disability form several challenges, despite evolutions in treatment options and risk assessment. The use of antilibidinal pharmacotherapy in this population is controversial and research is inconclusive about the most appropriate treatment strategy.
AIM
To highlight pharmacotherapeutic management of sexual behavior disorders in intellectual disability, its medical and ethical considerations.
METHOD
A literature review to provide an overview of the available literature, which was elaborated based on clinical experience.
RESULTS
We found a lack of scientific evidence on the efficacy of pharmacotherapy specifically for sexual behavior disorders in people with intellectual disabilities. The routine use of antilibidinal medication is contraindicated. Medical and ethical guidelines have been published as well as contraindications for initiating androgen deprivation therapy in the general population. The necessity of pharmacotherapy should be closely monitored and supplemented with psychotherapeutic care to cultivate the patient’s sexual skills, attitudes and knowledge. A distinction should be made between sexual behavior disorders of the ‘paraphilic type’ and of the ‘sexually maladjusted or naive type’.
CONCLUSION
Multidisciplinary evaluation, risk assessment and an individualized approach are the cornerstones of high-quality treatment of sexual behavior disorders in persons with intellectual disability.
Topics: Male; Humans; Intellectual Disability; Androgen Antagonists; Prostatic Neoplasms; Sexual Behavior; Psychotropic Drugs
PubMed: 38380485
DOI: No ID Found -
BMC Medical Genomics Oct 2023Intellectual disability (ID) is a heterogeneous condition affecting brain development, function, and/or structure. The X-linked mode of inheritance of ID (X-linked... (Review)
Review
Whole exome sequencing revealed variants in four genes underlying X-linked intellectual disability in four Iranian families: novel deleterious variants and clinical features with the review of literature.
AIM AND OBJECTIVE
Intellectual disability (ID) is a heterogeneous condition affecting brain development, function, and/or structure. The X-linked mode of inheritance of ID (X-linked intellectual disability; XLID) has a prevalence of 1 out of 600 to 1000 males. In the last decades, exome sequencing technology has revolutionized the process of disease-causing gene discovery in XLIDs. Nevertheless, so many of them still remain with unknown etiology. This study investigated four families with severe XLID to identify deleterious variants for possible diagnostics and prevention aims.
METHODS
Nine male patients belonging to four pedigrees were included in this study. The patients were studied genetically for Fragile X syndrome, followed by whole exome sequencing and analysis of intellectual disability-related genes variants. Sanger sequencing, co-segregation analysis, structural modeling, and in silico analysis were done to verify the causative variants. In addition, we collected data from previous studies to compare and situate our work with existing knowledge.
RESULTS
In three of four families, novel deleterious variants have been identified in three different genes, including ZDHHC9 (p. Leu189Pro), ATP2B3 (p. Asp847Glu), and GLRA2 (p. Arg350Cys) and also with new clinical features and in another one family, a reported pathogenic variant in the L1CAM (p. Glu309Lys) gene has been identified related to new clinical findings.
CONCLUSION
The current study's findings expand the existing knowledge of variants of the genes implicated in XLID and broaden the spectrum of phenotypes associated with the related conditions. The data have implications for genetic diagnosis and counseling.
Topics: Humans; Male; Intellectual Disability; Exome Sequencing; Iran; Mutation; Genes, X-Linked; Pedigree
PubMed: 37821930
DOI: 10.1186/s12920-023-01680-y -
American Journal of Medical Genetics.... Mar 2024Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual... (Review)
Review
Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess. We describe the phenotypic and genotypic data for 34 probands carrying CNVs in the 1q21.1 chromosome region (24 duplications, 8 deletions and 2 triplications). We also reviewed 89 duplications, 114 deletions and 5 triplications described in the literature, at variable 1q21.1 locations. We aimed to identify the most highly associated clinical features to determine the phenotypic expression in affected individuals. Developmental delay or learning disabilities and neuropsychiatric disorders were common in patients with deletions, duplications and triplications of 1q21.1. Mild dysmorphic features common in these CNVs include a prominent forehead, widely spaced eyes and a broad nose. The CNVs were mostly inherited from apparently unaffected parents. Almost half of the CNVs were distal, overlapping with a common minimal region of 1.2 Mb. We delineated the clinical implications of 1q21.1 CNVs and confirmed that these CNVs are likely pathogenic, although subject to incomplete penetrance and variable expressivity. Long-term follow-up should be performed to each newly diagnosed case, and prenatal genetic counseling cautiously discussed, as it remains difficult to predict the phenotype in the event of an antenatal diagnosis.
Topics: Humans; Female; Pregnancy; DNA Copy Number Variations; Phenotype; Genotype; Intellectual Disability; Prenatal Diagnosis
PubMed: 37881147
DOI: 10.1002/ajmg.a.63457 -
Pediatric Neurology Oct 2023This study aimed to examine the clinical usefulness of chromosome microarray (CMA) for selective implementation in patients with unexplained moderate or severe...
Chromosomal Aberrations in Pediatric Patients With Moderate/Severe Developmental Delay/Intellectual Disability With Abundant Phenotypic Heterogeneities: A Single-Center Study.
BACKGROUND
This study aimed to examine the clinical usefulness of chromosome microarray (CMA) for selective implementation in patients with unexplained moderate or severe developmental delay/intellectual disability (DD/ID) and/or combined with different dysphonic features in the Han Chinese population.
METHODS
We retrospectively analyzed data on 122 pediatric patients with unexplained isolated moderate/severe DD/ID with or without autism spectrum disorders, epilepsy, dystonia, and congenital abnormalities from a single-center neurorehabilitation clinic in southern China.
RESULTS
A total of 46 probands (37.7%) had abnormal CMA results among the 122 study patients. With the exclusion of aneuploidies, uniparental disomies, and multiple homozygotes, 37 patients harbored 39 pathogenic copy number variations (pCNVs) (median [interquartile range] size: 3.57 [1.6 to 7.1] Mb; 33 deletions and 6 duplications), enriched in chromosomes 5, 7, 15, 17, and 22, with a markedly high prevalence of Angelman/Prader-Willi syndrome (24.3% [nine of 37]). Three rare deletions in the regions 5q33.2q34, 17p13.2, and 13q33.2 were reported, with specific delineation of clinical phenotypes. The frequencies of pCNVs were 18%, 33.3%, 38.89%, 41.67%, and 100% for patients with 1, 2, 3, 4, and 5 study phenotypes, respectively; patients with more concomitant abnormalities in the heart, brain, craniofacial region, and/or other organs had a higher CMA diagnostic yield and pCNV prevalence (P < 0.05).
CONCLUSIONS
Clinical application of CMA as a first-tier test among patients with moderate/severe DD/ID combined with congenital structural anomalies improved diagnostic yields and the quality of clinical management in this series of patients.
Topics: Humans; Intellectual Disability; Developmental Disabilities; Retrospective Studies; DNA Copy Number Variations; Chromosome Aberrations; Phenotype
PubMed: 37566956
DOI: 10.1016/j.pediatrneurol.2023.06.001 -
Indian Journal of Pediatrics Jul 2024To determine the diagnostic yield of next generation sequencing (NGS) in patients with moderate/severe/profound intellectual disability (ID) unexplained by conventional...
OBJECTIVES
To determine the diagnostic yield of next generation sequencing (NGS) in patients with moderate/severe/profound intellectual disability (ID) unexplained by conventional tests and to assess the impact of definitive diagnosis on the clinical management and genetic counselling of these families.
METHODS
This was a ambi-directional study conducted at Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi. The study comprised 227 patients (prospective cohort - 126, retrospective cohort - 101) in whom NGS based tests were performed.
RESULTS
The mean age of study cohort was 4.5 ± 4.4 y (2.5 mo to 37.3 y). The male: female ratio was 1.6:1. The overall diagnostic yield of NGS was 53.3% (121/227) with causative variants identified in 84 known ID genes. Autosomal recessive intellectual disability (ARID) (23.3%, 53/227) was the most common followed by autosomal dominant intellectual disability (ADID) (20.7%, 47/227) and X-linked intellectual disability (XLID) (9.2%, 21/227). The diagnostic yield was notably higher for ID plus associated condition group (55.6% vs. 20%) (p = 0.0075, Fisher's exact test) compared to isolated ID group. The impact of diagnosis on active or long-term management was observed in 17/121 (14%) and on reproductive outcomes in 26/121 (21.4%) families.
CONCLUSIONS
There is paucity of data on molecular genetic spectrum of ID from India. The current study identifies extensive genetic heterogeneity and the impact of NGS in patients with ID unexplained by standard genetic tests. The study identified ARID as the most common cause of ID with additional implications for reproductive outcomes. It reiterates the importance of phenotype in genetic testing.
Topics: Humans; Intellectual Disability; Male; Female; High-Throughput Nucleotide Sequencing; Child; Child, Preschool; Adolescent; Infant; Adult; Young Adult; Retrospective Studies; Genetic Testing; India; Prospective Studies; Genetic Counseling
PubMed: 37804371
DOI: 10.1007/s12098-023-04820-5 -
Journal of Psychopathology and Clinical... Aug 2023Sotos syndrome (Sotos) and Tatton-Brown-Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with...
Sotos syndrome (Sotos) and Tatton-Brown-Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with these syndromes tend to have similar cognitive profiles and high likelihood of autism symptomatology. However, whether and how sensory processing is affected is currently unknown. Parents/caregivers of 36 children with Sotos and 20 children with TBRS completed the Child Sensory Profile-2 (CSP-2) and the Sensory Behavior Questionnaire (SBQ) along with other standardized questionnaires assessing autistic traits (Social Responsiveness Scale, Second Edition, SRS-2), attention deficit hyperactivity disorder (ADHD) traits (Conners 3), anxiety (Spence Children's Anxiety Scale, Parent Version, SCAS-P), and adaptive behavior (Vineland Adaptive Behavior Scales Third Edition). Sensory processing differences were clearly evident in both syndromes, though there was significant variation in both cohorts. SBQ data indicated that both the and of sensory behavior were more severe when compared to neurotypicals, with levels of sensory behavior impact and frequency being similar to autistic children. CSP-2 data indicated 77% of children with Sotos and 85% children with TBRS displayed clear differences in sensory Registration (missing sensory input). Clear differences relating to Body Position (proprioceptive response to joint and muscle position; 79% Sotos; 90% TBRS) and Touch (somatosensory response to touch on skin; 56% Sotos; 60% TBRS) were also particularly prevalent. Correlation analyses demonstrated that in both syndromes sensory processing differences tend to be associated with difficulties relating to autistic traits, anxiety, and some domains of ADHD. In Sotos, sensory processing differences were also associated with lower adaptive behavior skills. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with Sotos and TBRS, demonstrates that sensory processing differences have a profound impact on everyday life. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Topics: Child; Humans; Intellectual Disability; Sotos Syndrome; Abnormalities, Multiple; Touch; Musculoskeletal Abnormalities; Touch Perception
PubMed: 37289542
DOI: 10.1037/abn0000837 -
Journal of Intellectual Disability... Oct 2023Family-systems interventions have been proposed as one way of supporting families of people with an intellectual disability (ID) or who are autistic. This systematic... (Review)
Review
BACKGROUND
Family-systems interventions have been proposed as one way of supporting families of people with an intellectual disability (ID) or who are autistic. This systematic review aimed to summarise what family-systems interventions have been studied with this population, what evidence there is for their effectiveness and families' experiences of the interventions.
METHODS
The review was preregistered on PROSPERO (CRD42022297516). We searched five electronic databases, identified 6908 records and screened 72 full texts. Study quality was evaluated using the Mixed Methods Appraisal Tool, and a narrative synthesis was used.
RESULTS
We identified 13 eligible articles with 292 participating families. Most studies reported positive effects of the interventions on wellbeing and family relationships, and families reported positive experiences. However, research quality was poor and there are no any sufficiently powered randomised controlled trials demonstrating family-systems interventions' effectiveness for this population.
CONCLUSIONS
There is a need for higher-quality research to establish whether family-systems interventions are beneficial for families of people who have an ID or who are autistic.
Topics: Humans; Intellectual Disability; Autistic Disorder
PubMed: 37532456
DOI: 10.1111/jir.13068