No approved-drug candidate for microcephaly-thin corpus callosum-intellectual disability syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
The condition described in these abstracts is not a single named syndrome but a set of overlapping findings: corpus callosum abnormalities (agenesis, dysgenesis, short or dysplastic corpus callosum), intellectual disability, speech impairment, and sometimes autism. In a 2011 study of one translocation patient and seven unpublished deletion patients, haploinsufficiency of the ARID1B gene was associated with corpus callosum abnormalities, intellectual disability, severe speech impairment, and autism. A 2016 study of 177 individuals with corpus callosum anomalies and intellectual disability found pathogenic ARID1B mutations in 10 of 99 index cases (10%) with unexplained anomalies, and in 11 of 153 (7.2%) when excluding patients with chromosomal imbalances. Taking the full series of 177, ARID1B mutations accounted for 6.2% of cases. The authors concluded that ARID1B mutations are likely the main genetic cause of corpus callosum anomalies with intellectual disability. Among 64 previously reported patients with Coffin-Siris syndrome due to ARID1B mutations, 39% had corpus callosum anomalies.
A 2023 study identified bi-allelic variants in a different gene, WDR47, in four unrelated families presenting with corpus callosum dysgenesis together with microcephaly, cerebellar abnormalities, and hydrocephalus. Mouse models showed that WDR47 is required for survival of callosal neurons by maintaining mitochondrial and microtubule homeostasis. The severity of the corpus callosum phenotype depended on the degree of loss of function caused by the human variants. A 2024 study of 15 children and adolescents (8–15 years) with developmental absence of the corpus callosum found reduced receptive and expressive language compared with test norms, and high rates of language and communication impairments. Complete agenesis, higher social risk, and lower non-verbal IQ were associated with communication difficulties. A 2020 case report described an 8-year-old boy with isolated total agenesis of the corpus callosum and normal intelligence, but the authors stressed that isolated agenesis is not innocuous and requires strict neurocognitive follow-up, as deficits may emerge during adolescence.
What is still missing is a unified clinical definition of the syndrome, prospective data on the full range of outcomes in children with ARID1B mutations, and any trial design or intervention strategy. No drug is mentioned in any of these abstracts. The genetic heterogeneity is extreme — more than 70 single gene mutations and copy number variations are known, and most cases remain unexplained. Money for large-scale sequencing of unexplained cases, for longitudinal neurocognitive follow-up, and for patient stratification by genotype is lacking.
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Clinical Genetics · 2011 · 143 citations · open access
Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of <i>ARID1B</i>
AbstractCorpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.
https://doi.org/10.1111/j.1399-0004.2011.01755.xBrain · 2016 · 36 citations
<i>ARID1B</i>mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability
AbstractSir, In their extensive review article in Brain, Edwards et al. (2014) presented physiological processes underlying the formation of the corpus callosum, as well as pathological conditions in mice and humans leading to agenesis of the corpus callosum (AgCC). They reviewed most human syndromes associated with AgCC and emphasized the great heterogeneity of known genetic causes of AgCC in humans by listing more than 70 single gene mutations and copy number variations (CNV), which altogether explain 30–45% of all cases. Most of these genetic anomalies are responsible for AgCC associated with other cerebral or extra-cerebral malformations and/or intellectual disability (ID). The association between AgCC and intellectual disability is further highlighted by the higher prevalence of AgCC in individuals with intellectual disability (2–3%) versus in the general population (0.025–0.02%) (Paul et al., 2007; Sotiriadis and Makrydimas, 2012). Thereby, given the extreme genetic heterogeneity of intellectual disability (Deciphering Developmental Disorders Study, 2015) and the number of genes involved in the formation of the corpus callosum in humans, it is not surprising that genetic causes of syndromes associating AgCC and intellectual disability are so numerous. However, the prevalence of each of these genetic anomalies in individuals with this association is currently unknown. To improve our knowledge on genetic causes of AgCC with intellectual disability, we collected prospectively clinical and molecular data from 177 individuals with anomalies of the corpus callosum (ACC, comprising patients with AgCC, or with short corpus callosum or with dysplastic corpus callosum), and intellectual disability (or developmental delay for young children; ACC-ID) between 2009 and 2015. A clinical diagnosis, further confirmed by targeted sequencing of the corresponding gene, when possible, was made for 15 patients. Among these patients, one had a diagnosis of Coffin-Siris syndrome (CSS) and a mutation in ARID1B, the major gene for Coffin-Siris syndrome accounting for 40% (Wieczorek et al., 2013) to 68% (Santen et al., 2013) of all cases. Coffin-Siris syndrome was suspected in four other patients whose DNA samples were studied on our gene panel (see below). Excluding these patients as well as patients with causal chromosomal abnormalities detected by karyotyping or SNP arrays (n = 24; chromosomal microarray analysis was performed in all patients, none with deletion of ARID1B), the cause of ACC-ID remained unknown in 138 patients (Supplementary Fig. 1). The main pitfalls possibly explaining the low diagnosis yield with the ‘targeted strategy’ were the extreme heterogeneity of ACC-ID, the limited knowledge on the genetic bases of the hundreds of clinical entities associated with ACC at that time and the limited availability of genetic testing. We then undertook a molecular study of 99 index cases with unexplained ACC-ID using next generation sequencing of 423 selected genes involved in ACC in humans or mice. As expected, we found very few recurrent genes, except ARID1B, which proved to be prominently involved. Indeed, we found pathogenic mutations in ARID1B in 10 additional patients (10%). Clinical and molecular findings in 10 patients with ARID1B mutation and ACC-ID.Top row: Facial dysmorphy is consistent with the diagnosis of Coffin-Siris syndrome in all patients. Middle row: Brain MRI showed anomalies of the corpus callosum in all patients with Patient 2 having a short corpus callosum. Bottom row: Electrophoregrams showing de novo heterozygous ARID1B mutations in all probands and a maternally inherited mutation in Patient 11 (de novo in the mother). MGF = maternal grandfather; MGM = maternal grandmother. Paternal DNA of Patient 9 was not available. Molecular and clinical data of 11 patients with ACC-ID and a diagnosis of Coffin-Siris syndrome due to ARID1B mutations CC = corpus callosum; ACC = anomalies of the corpus callosum; perc. = percentile; neon. feed. diff. = neonatal feeding difficulties. Molecular and clinical data of 11 patients with ACC-ID and a diagnosis of Coffin-Siris syndrome due to ARID1B mutations CC = corpus callosum; ACC = anomalies of the corpus callosum; perc. = percentile; neon. feed. diff. = neonatal feeding difficulties. Thus, the overall prevalence of ARID1B mutations in our series of studied patients with unexplained ACC-ID is 10% (10/99), 7.2% (11/153) in patients with ACC-ID unexplained by chromosomal imbalance and 6.2% (11/177) taking the complete series into account. These results imply that mutations in ARID1B are likely the main cause of ACC-ID. ARID1B is one of the major genes explaining intellectual disability, with up to 0.5–1% of patients with intellectual disability carrying pathogenic ARID1B mutations in large-scale studies (Hoyer et al., 2012; Deciphering Developmental Disorders Study, 2014). Considering 64 patients with a CSS phenotype and mutations in ARID1B only (i.e. excluding patients with chromosomal deletion encompassing the gene and patients with anomalies in other Coffin-Siris syndrome genes) reported in six articles (Hoyer et al., 2012; Santen et al., 2012, 2013; Tsurusaki et al., 2012, 2014; Wieczorek et al., 2013), the proportion of CSS patients with ACC is 39% (25/64). This high proportion of ACC in patients with CSS due to ARID1B mutations combined with the relatively high prevalence of ARID1B de novo mutations in individuals with intellectual disability explains the prominent position of ARID1B in the diagnosis of ACC-ID. ARID1B encodes a subunit of the SWI/SNF-like BAF chromatin remodelling complex comprising other components (ARID1A, SMARCA2, SMARCA4, SMARCB1, SMARCE1), in which mutations are also responsible for Coffin-Siris syndrome (with or without ACC) or for its main differential diagnosis, Nicolaides-Baraister syndrome. Though mutations in genes encoding for these proteins may be associated with ACC-ID (Kosho et al., 2013,;Santen et al., 2013; Wieczorek et al., 2013), none were found in our series, which is likely explained by their rarity. These results have important implications for prenatal counselling when ACC (mainly AgCC) is diagnosed pre-natally. The finding of the aetiology of a prenatally diagnosed ACC and the establishment of the foetal intellectual prognosis have major impact on the parental decision to continue or terminate the pregnancy. While the finding of another visceral or brain malformation usually worsens the cognitive prognosis, parental decision-making is particularly difficult when the ACC is apparently isolated (i.e. not associated with other cerebral or extra-cerebral malformations). In the latter case, prenatal counselling is based on statistical data showing that ∼70% of children born after the identification of isolated ACC have a normal intellectual development (Moutard et al., 2012; Sotiriadis and Makrydimas, 2012). The Coffin-Siris syndrome phenotype is mainly identified in children with subtle morphological features of the face and extremities not detectable on prenatal echography and is not frequently associated with other (cerebral or extra-cerebral) malformations when a mutation in ARID1B is causative (Hoyer et al., 2012; Santen et al., 2013; Wieczorek et al., 2013; Tsurusaki et al., 2014). Likewise, the patients of our series with ARID1B mutations have a mild phenotype since they do not have gross malformations. Accordingly, those with an antenatal diagnosis of AgCC had isolated AgCC. These data further explain the lack of patients with mutations in other Coffin-Siris syndrome-causing genes in our series: the absence of associated malformation may have influenced the choice of parents facing the discovery of foetal ACC towards pregnancy continuation and thus increased the proportion of ARID1B mutations in patients with ACC-ID. Given the prevalence of ARID1B mutations in ACC-ID and the scarcity of additional malformations in Coffin-Siris syndrome related to ARID1B, our study suggests that the sequencing of ARID1B—and of other genes to be determined—could be performed in cases of foetal ACC along with CGH-array and morphological investigations, in order to improve the accuracy of the intellectual prognosis. This study was financially supported by the Assistance Publique des Hôpitaux de Paris (APHP), PHRC (n°PO81260), the Fondation Maladies Rares, the Agence de la Biomédecine AOR 2012, the Agence Nationale de la Recherche (ANR Blanc 2013 CILAXCAL), and the “Investissements d’Avenir” programme ANR-10-IAIHU-06 (IHU-A-ICM). C.D. and C.N. are members of the Bio-Psy Labex. S.H. is supported by a master grant and C.A. by a doctoral grant from the Fondation pour la Recherche Médicale (FRM). Supplementary material is available at Brain online.
https://doi.org/10.1093/brain/aww181Neurosciences · 2001 · 18 citations · open access
Corpus callosum agenesis
AbstractOBJECTIVE: The objectives are to analyse corpus callosum agenesis in children with various neurological problems in a hospital set-up, and to study the neurological and systemic abnormalities associated with this condition. METHODS: The children with various neurological problems who underwent computerized tomography brain from January 1993 to December 1997, and were found to have corpus callosum agenesis, formed the subjects of this study. These children were examined for any syndromic association, congenital infections or metabolic defects. RESULTS: Out of 2164 children who underwent computerized tomography brain, 22 had corpus callosum agenesis (1%). Most cases were not syndromic and 64% were males. Epileptic disorders were noted in about one third of cases. CONCLUSION: Corpus callosum agenesis an important anomaly in children with neurodevelopment handicaps, usually detected by neuroradiology.
https://doi.org/10.17712/1658-3183.1084Journal of Medical Case Reports · 2020 · 16 citations · open access
Isolated agenesis of the corpus callosum and normal general intelligence development during postnatal life: a case report and review of the literature
AbstractBACKGROUND: Agenesis of the corpus callosum can occur isolated or as part of a complex congenital syndrome. Patients with isolated agenesis of the corpus callosum may present with severe intellectual disability, although a proportion of affected individuals develop normal intelligence. However, even in patients with no apparent deficits, subtle neuropsychological alterations may occur as the cognitive demand increases with age. Hence, patients with this deffect require a strict follow-up during their postnatal life. Thus, physicians require a better knowledge of the cognitive features of agenesis of the corpus callosum to improve their approach to this cerebral malformation. Here, we report an illustrative case of a school-age child with isolated agenesis of the corpus callosum and normal intelligence. We also provide a literature review about the postnatal screening of neurocognitive deficits in patients with agenesis of the corpus callosum. CASE PRESENTATION: An 8-year-old Hispanic boy with total agenesis of the corpus callosum attended for medical follow-up. The defect was identified during the neonatal period by cranial ultrasonography and brain computed tomography scan. However, he did not present any craniofacial or non-cerebral malformation suggestive of a congenital syndrome. Furthermore, he showed no neuropsychiatric disorder or intellectual disability during his early childhood. At the age of 4, he was subjected to a control brain magnetic resonance imaging that showed total agenesis of the corpus callosum and colpocephaly. At his arrival, a neurological examination was normal with no signs of intracranial hypertension. His intelligence quotient was unaltered and he scored normal in the Mini-Mental State Examination test. The literature reviewed here suggested that patients with agenesis of the corpus callosum require a strict neurocognitive follow-up during postnatal life, as they may present neuropsychological deficits during adolescence, when development of the corpus callosum is completed and there is maximum reliance on this structure. Thus, our patient was scheduled for future annual neurocognitive testing. CONCLUSIONS: Isolated agenesis of the corpus callosum is not innocuous, and patients with this defect require a strict neurocognitive follow-up. We provide an informative reference tool useful for the postnatal neuropsychological screening of patients with isolated agenesis of the corpus callosum.
https://doi.org/10.1186/s13256-020-2359-2Brain and Language · 2024 · 3 citations · open access
Language and communication functioning in children and adolescents with agenesis of the corpus callosum
AbstractThe corpus callosum, the largest white matter inter-hemispheric pathway, is involved in language and communication. In a cohort of 15 children and adolescents (8-15 years) with developmental absence of the corpus callosum (AgCC), this study aimed to describe language and everyday communication functioning, and explored the role of anatomical factors, social risk, and non-verbal IQ in these outcomes. Standardised measures of language and everyday communication functioning, intellectual ability and social risk were used. AgCC classification and anterior commissure volume, a potential alternative pathway, were extracted from T1-weighted images. Participants with AgCC showed reduced receptive and expressive language compared with test norms, and high rates of language and communication impairments. Complete AgCC, higher social risk and lower non-verbal IQ were associated with communication difficulties. Anterior commissure volume was not associated with language and communication. Recognising heterogeneity in language and communication functioning enhances our understanding and suggests specific focuses for potential interventions.
https://doi.org/10.1016/j.bandl.2024.105448Physical Therapy · 1967 · 0 citations
Book Reviews
AbstractJournal Article Book Reviews Get access Functions of the Corpus Callosum. Edited by E. G. Ettlinger, M.A., Ph.D., Little, Brown and Company, Boston, 1965. Paper, illus., 152 pp., $3.75. Kathryn J. Shaffer, M.S. Kathryn J. Shaffer, M.S. Search for other works by this author on: Oxford Academic Google Scholar Physical Therapy, Volume 47, Issue 9, September 1967, Page 884, https://doi.org/10.1093/ptj/47.9.884 Published: 01 September 1967
https://doi.org/10.1093/ptj/47.9.884bioRxiv (Cold Spring Harbor Laboratory) · 2023 · 0 citations · open access
Bi-allelic variants in <i>WDR47</i> lead to neuronal loss causing a rare neurodevelopmental syndrome with corpus callosum dysgenesis in humans
AbstractABSTRACT The corpus callosum (CC) is the largest interhemispheric connection that is largely formed by the axons of layer 2/3 callosal projection neurons (CPNs) through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps may prevent the proper development of the corpus callosum resulting in a spectrum of disorders collectively referred to as corpus callosum dysgenesis (CCD). Here, we report four unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly, cerebellar abnormalities and hydrocephalus. Using a combination of in vitro and in vivo mouse models and complementation assays, we show that independently from its previously identified functions in neuronal migration and axonal extension, WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further provide evidence that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.
https://doi.org/10.1101/2023.12.22.572779Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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