Mutations Affecting the SAND Domain of DEAF1 Cause Intellectual Disability with Severe Speech Impairment and Behavioral Problems

The 15q11.2 breakpoint (BP) 1–BP2 deletion syndrome is emerging as the most frequent pathogenic copy number variation in humans related to neurodevelopmental diseases, with changes in cognition, behavior, and brain morphology. Previous publications have reported that patients with 15q11.2 BP1–BP2 deletion showed intellectual disability (ID), speech impairment, developmental delay (DD), and/or behavioral problems. We describe three new cases, aged 3 or 6 years old and belonging to three unrelated Korean families, with a 350-kb 15q11.2 BP1–BP2 deletion of four highly conserved genes, namely, the TUBGCP5, CYFIP1, NIPA2, and NIPA1 genes. All of our cases presented with global DD and/or ID, and the severity ranged from mild to severe, but common facial dysmorphism and congenital malformations in previous reports were not characteristic. The 15q11.2 BP1–BP2 deletion was inherited from an unaffected parent in all cases. Our three cases, together with previous findings from the literature review, confirm some of the features earlier reported to be associated with 15q11.2 BP1–BP2 deletion and help to further delineate the phenotype associated with 15q11.2 deletion. Identification of more cases with 15q11.2 BP1–BP2 deletion will allow us to obtain a better understanding of the clinical phenotypes. Further explanation of the functions of the genes within the 15q11.2 BP1–BP2 region is required to resolve the pathogenic effects on neurodevelopment.

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Behavioral problems in people with intellectual disability: Basic facts, incidence and risk factors

Specijalna edukacija i rehabilitacija ◽

10.5937/specedreh12-3395 ◽

2013 ◽

Vol 12 (2) ◽

pp. 203-219

Author(s):

Buha Natasa ◽

Gligorovic Milica

Keyword(s):

Risk Factors ◽

Intellectual Disability ◽

Behavioral Problems ◽

Basic Facts

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Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing Primary microcephaly in consanguineous Pakistani families

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.38.1.4464 ◽

2021 ◽

Vol 38 (1) ◽

Author(s):

Ehtisham ul Haq Makhdoom ◽

Haseeb Anwar ◽

Shahid Mahmood Baig ◽

Ghulam Hussain

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Speech Impairment ◽

Primary Microcephaly ◽

Rare Mutation ◽

Homozygous Variant ◽

Whole Exome ◽

Pakistani Families

Background & Objectives: Primary Microcephaly (MCPH) is a rare neurogenetic disease, manifesting congenitally reduced head circumference and non-progressive intellectual disability (ID). To date, twenty-eight genes with biallelic mutations have been reported for this disorder. The study aimed for molecular genetic characterization of Pakistani families segregating MCPH. Methods: We studied two unrelated consanguineous families (family A and B) presenting >2 patients with diagnostic symptoms of MCPH, born to asymptomatic parents. We employed whole-exome sequencing (WES) of probands to find putative causal mutations. The candidate variants were further confirmed and analyzed for co-segregation by Sanger sequencing of all available members of each family. This study was conducted at Government College University, Faisalabad, Pakistan, and Cologne Center for Genomics (CCG), University of Cologne, Germany; during 2017-2020. Results: We identified a novel homozygous variant c.10097_10098delGA, p.(Gly3366Glufs*19) in exon 26 of ASPM gene in family A which presents with moderate intellectual disability, speech impairment, visual abnormalities, seizures, and ptyalism. Family B was found to segregate nonsense, homozygous variant c.448C>T p.(Arg150*) in CDK5RAP2. The patients also exhibited mild to severe seizures without ptyalism that has not been previously reported in patients with mutations in the CDK5RAP2 gene. Conclusion: We report a novel mutation in ASPM and ultra-rare mutation in the CDK5RAP2 gene, both causing primary microcephaly. The study expands the mutational spectrum of the ASPM gene to 212, and also adds to the clinical spectrum of CDK5RAP2 mutations. It also demonstrated the utility of WES in the investigation and genetic diagnosis of genetically heterogeneous disorders like MCPH. These findings would aid in diagnostic and preventive strategies including carrier screening, cascade testing, and genetic counselling. doi: https://doi.org/10.12669/pjms.38.1.4464 How to cite this:Makhdoom EH, Anwar H, Baig SM, Hussain G. Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing Primary microcephaly in consanguineous Pakistani families. Pak J Med Sci. 2022;38(1):---------. doi: https://doi.org/10.12669/pjms.38.1.4464 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Intellectual disability and mental disorders in a US population representative sample of adolescents

Psychological Medicine ◽

10.1017/s0033291718001605 ◽

2018 ◽

Vol 49 (6) ◽

pp. 952-961 ◽

Cited By ~ 9

Author(s):

Jonathan M. Platt ◽

Katherine M. Keyes ◽

Katie A. McLaughlin ◽

Alan S. Kaufman

Keyword(s):

Bipolar Disorder ◽

Intellectual Disability ◽

Mental Disorders ◽

Mental Disorder ◽

Behavioral Problems ◽

Behavior Disorders ◽

Representative Sample ◽

Age Of Onset ◽

Population Sample ◽

Clinical Samples

AbstractBackgroundMost research on the prevalence, distribution, and psychiatric comorbidity of intellectual disability (ID) relies on clinical samples, limiting the generalizability and utility of ID assessment in a legal context. This study assessed ID prevalence in a population-representative sample of US adolescents and examined associations of ID with socio-demographic factors and mental disorders.MethodsData were drawn from the National Comorbidity Survey Adolescent Supplement (N= 6256). ID was defined as: (1) IQ ⩽ 76, measured using the Kaufman Brief Intelligence Test; (2) an adaptive behavior score ⩽76, and (3) age of onset ⩽18 measured using a validated scale. The Composite International Diagnostic Interview assessed 15 lifetime mental disorders. The Sheehan disability scale assessed disorder severity. We used logistic regression models to estimate differences in lifetime disorders for adolescents with and without ID.ResultsID prevalence was 3.2%. Among adolescents with ID, 65.1% met lifetime criteria for a mental disorder. ID status was associated with specific phobia, agoraphobia, and bipolar disorder, but not behavior disorders after adjustment for socio-demographics. Adolescents with ID and mental disorders were significantly more likely to exhibit severe impairment than those without ID.ConclusionsThese findings highlight how sample selection and overlap between ID and psychopathology symptoms might bias understanding of the mental health consequences of ID. For example, associations between ID and behavior disorders widely reported in clinical samples were not observed in a population-representative sample after adjustment for socio-demographic confounders. Valid assessment and understanding of these constructs may prove influential in the legal system by influencing treatment referrals and capital punishment decisions.General Scientific SummaryCurrent definitions of intellectual disability (ID) are based on three criteria: formal designation of low intelligence through artificial problem-solving tasks, impairment in one's ability to function in his/her social environment, and early age of onset. In a national population sample of adolescents, the majority of those with ID met criteria for a lifetime mental disorder. Phobias and bipolar disorder, but not behavior disorders, were elevated in adolescents with ID. Findings highlight the need to consider how behavioral problems are conceptualized and classified in people with ID.

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Antipsychotic Drug Prescription and Behavioral Problems in Individuals with Intellectual Disability

NeuroPsychopharmacotherapy ◽

10.1007/978-3-319-56015-1_445-1 ◽

2021 ◽

pp. 1-21

Author(s):

Gerda Margaretha de Kuijper ◽

Albert Willem Lenderink

Keyword(s):

Intellectual Disability ◽

Antipsychotic Drug ◽

Behavioral Problems ◽

Drug Prescription

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Dystrophinopathy in a Family Due to a Rare Nonsense Mutation Causing Predominant Behavioral Phenotype

Journal of Pediatric Neurology ◽

10.1055/s-0039-1698437 ◽

2019 ◽

Vol 18 (04) ◽

pp. 210-213

Author(s):

Yohei Harada ◽

Seth T. Sorensen ◽

Akilandeswari Aravindhan ◽

Vikki Stefans ◽

Aravindhan Veerapandiyan

Keyword(s):

Intellectual Disability ◽

Muscular Dystrophy ◽

Behavioral Problems ◽

Nonsense Mutation ◽

Neuromuscular Disorders ◽

Elevated Serum ◽

Becker Muscular Dystrophy ◽

Genetic Changes ◽

Dmd Gene ◽

Neurobehavioral Deficits

AbstractDystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DMD gene that encodes dystrophin. The clinical spectrum includes Duchenne muscular dystrophy, Becker muscular dystrophy, X-linked cardiomyopathy, and intellectual disability without involvement of skeletal muscle. Cognitive and behavioral problems are commonly seen among patients with dystrophinopathy. DMD gene is the largest human gene, consisting of 79 exons that produce dystrophin protein. Patients with genetic changes involving shorter dystrophin isoforms such as Dp140 and Dp71 are suggested to have higher rates of intellectual disability, attention-deficit/hyperactivity disorder, and other neuropsychiatric comorbidities. We describe three brothers who presented with prominent neurobehavioral deficits of varying degree, mild proximal weakness, and elevated serum creatine kinase due to a rare nonsense mutation, c.1702C > T; p.Gln568X, in exon 14 of DMD gene. Further studies are needed to better understand the effects of this rare mutation.

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A Novel SETBP1 Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder

Journal of Pediatric Genetics ◽

10.1055/s-0040-1715639 ◽

2020 ◽

Author(s):

Ivona Vrkić Boban ◽

Futoshi Sekiguchi ◽

Mirela Lozić ◽

Noriko Miyake ◽

Naomichi Matsumoto ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Dominant ◽

De Novo ◽

Chromosomal Abnormalities ◽

Chromosome Translocation ◽

Behavioral Disorder ◽

Behavioral Difficulties ◽

Speech Impairment ◽

Balanced Translocation ◽

Severe Intellectual Disability

AbstractBalanced chromosomal abnormalities (BCAs) can disrupt gene function resulting in disease. To date, BCA disrupting the SET binding protein 1 (SETBP1) gene has not been reported. On the other hand, de novo heterozygous variants in the highly conserved 11-bp region in SETBP1 can result in the Schinzel–Giedion syndrome. This condition is characterized by severe intellectual disability, a characteristic face, and multiple-system anomalies. Further other types of mutations involving SETBP1 are associated with a different phenotype, mental retardation, autosomal dominant 29 (MRD29), which has mild dysmorphic features, developmental delay, and behavioral disorders. Here we report a male patient who has moderate intellectual disability, mild behavioral difficulties, and severe expressive speech impairment resulting from a de novo balanced chromosome translocation, t(12;18)(q22;q12.3). By whole genome sequencing, we determined the breakpoints at the nucleotide level. The 18q12.3 breakpoint was located between exons 2 and 3 of SETBP1. Phenotypic features of our patient are compatible with those with MRD29. This is the first reported BCA disrupting SETBP1.

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