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Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been described as an autosomal-dominant disorder caused by mutations in the NR2F1 gene, whose common characteristics include developmental delay, intellectual disability, optic nerve atrophy, hypotonia, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity and thinning of the corpus callosum. Missense mutations in NR2F1 have been reported to be the major cause of BBSOAS. A possible genotype-phenotype correlation has been considered with missense mutations affecting the ligand-binding domain of NR2F1 as well as whole-gene deletions of NR2F1 showing a milder phenotype of BBSOAS. Here we report on a patient with a novel frameshift mutation in NR2F1 showing the full spectrum of BBOAS indicating an expanded clinical spectrum and a reconsideration of the observed genotype-phenotype correlation., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain threshold were described as additional characteristic features and the disorder was subsequently termed "intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)" in the OMIM database (MIM # 617450). Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the last exon of PPM1D. While the patient showed features overlapping with the reported phenotype, such as a short stature and small hands and feet, he also presented with additional features like cleft lip and palate and an aberrant right subclavian artery. Notably, the patient did not have any gastrointestinal difficulties or periods of fever, indicating variability of the phenotype of patients with PPM1D mutations., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Interstitial deletions including chromosome region 1q23.3q24.1 are rare. Only eight patients with molecularly characterized deletions have been reported to date. Their phenotype included intellectual disability/developmental delay, growth retardation, microcephaly, congenital heart disease, and renal malformations. We report on a female patient with mild developmental delay, congenital heart disease, and bilateral renal hypoplasia in whom an interstitial de novo deletion of approximately 2.7 Mb in 1q23.3q24.1 was detected by array CGH. This is the smallest deletion described in this region so far. Genotype-phenotype comparison with previously published patients allowed us to propose LMX1A and RXRG as potential candidate genes for intellectual disability, PBX1 as a probable candidate gene for renal malformation, and enabled us to narrow down a chromosome region associated with microcephaly. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Retinitis pigmentosa in combination with hearing loss can be a feature of different Mendelian disorders. We describe a novel syndrome caused by biallelic mutations in the 'exosome component 2' (EXOSC2) gene., Methods: Clinical ascertainment of three similar affected patients followed by whole exome sequencing., Results: Three individuals from two unrelated German families presented with a novel Mendelian disorder encompassing childhood myopia, early onset retinitis pigmentosa, progressive sensorineural hearing loss, hypothyroidism, short stature, brachydactyly, recognisable facial gestalt, premature ageing and mild intellectual disability. Whole exome sequencing revealed homozygous or compound heterozygous missense variants in the EXOSC2 gene in all three patients. EXOSC2 encodes the 'ribosomal RNA-processing protein 4' (RRP4)-one of the core components of the RNA exosome. The RNA exosome is a multiprotein complex that plays key roles in RNA processing and degradation. Intriguingly, the EXOSC2-associated phenotype shows only minimal overlap with the previously reported diseases associated with mutations in the RNA exosome core component genes EXOSC3 and EXOSC8., Conclusion: We report a novel condition that is probably caused by altered RNA exosome function and expands the spectrum of clinical consequences of impaired RNA metabolism., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The clinical diagnosis of Lujan-Fryns syndrome (LFS) comprises X-linked intellectual disability (XLID) with marfanoid habitus, distinct combination of minor facial anomalies and nasal speech. However the definition of syndrome was significantly broadened since the original report and implies ID with marfanoid habitus. Mutations of three genes (MED12, UPF3B, and ZDHHC9) have been reported in "broadly defined" LFS. We examined these genes in 28 individuals with a tentative clinical diagnosis of LFS but we did not identify any causative mutation. By molecular karyotyping we detected other disorders, i.e., Phelan-McDermid syndrome and 16p11.2 microduplication, each in one patient. One affected individual was carrier of a different recurrent duplication on 16p11.2 that has been reported several times to the DECIPHER and ISCA databases in individuals with autism, intellectual disability (ID), and developmental delay. It may represent a new duplication syndrome. We also identified previously unreported de novo duplication on chromosome 12p13.31 which we considered to be disease-causing. X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each. While LFS is defined as a form of XLID, there seem to be various conditions that have rather similar phenotypes. Therefore, the combination of ID and marfanoid habitus in a male patient is not sufficient for the diagnosis of LFS. We suggest that the diagnosis of LFS in patients with ID and marfanoid habitus should be made only in presence of specific facial features, nasal speech and obvious X-linked segregation of the disorder or an unambiguously pathogenic mutation in the MED12., (© 2015 Wiley Periodicals, Inc.)

Interstitial deletions on the long arm of chromosome six have been described for several regions including 6q16, 6q22.1, and 6q21q22.1, and with variable phenotypes such as intellectual disability/developmental delay, growth retardation, major and minor facial anomalies. However, an isolated microdeletion of the sub-band 6q22.33 has not been reported so far and thus, no information about the specific phenotype associated with such a copy number variant is available. Here, we define the clinical picture of an isolated 6q22.33 microdeletion based on the phenotype of six members of one family with loss of approximately 1 Mb in this region. Main clinical features include mild intellectual disability and behavioral abnormalities as well as microcephaly, heart defect, and cleft lip and palate., (© 2015 Wiley Periodicals, Inc.)

We report on the clinical data and molecular cytogenetic findings in three unrelated patients presenting with intellectual disability and behavior abnormalities. An overlapping microduplication involving 3p26.2-26.3 was identified in these patients. All three aberrations were confirmed and proven to be parentally inherited. The sizes of the duplications were different, with a common minimal region of 423,754 bp containing two genes - TRNT1 and CRBN. Here, we hypothesize that the copy number gain of CRBN gene might be responsible for developmental delay/intellectual disability., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

We report on a de novo 0.5 Mb triplication (partial tetrasomy) of chromosome 17q25.3 in a 10-year-old girl with severe intellectual disability, infantile seizures (West syndrome), moderate hearing loss, Dandy-Walker malformation, microcephaly, craniofacial dysmorphism, striking cutaneous syndactyly (hands 3-4, feet 2-3), joint laxity, and short stature. The triplication resulted from the unusual combination of a terminal duplication at 17qter and a cryptic translocation of an extra copy of the same segment onto chromosome 10qter. The breakpoint at 17q25.3 was located within the FOXK2 gene. SNP chip analysis suggested that the rearrangement occurred during paternal meiosis involving both paternal chromosomes 17., (© 2013 Wiley Periodicals, Inc.)

We report about the partial de novo loss of GLRB and GRIA2 in an individual with intellectual disability (ID). No additional mutations were found in either gene. GLRB itself does not seem to be a good candidate as it causes autosomal recessive hyperekplexia and no symptoms were found in the patient. Mutations of GRIA2 have not been described as cause of ID to date. Nonetheless, it is a very attractive candidate because it encodes a subunit of a glutamate receptor, which is highly expressed in postsynaptic structures and has an important role in signal transduction across synapses. Although we were able to isolate a fragment of a fusion transcript of both genes from the patient's blood, we were not able to isolate a transcript with an open reading frame throughout the entire length. The reading frame could be restored by differential splicing, which might take place in brain tissue but not in blood. We assume that either haploinsufficiency of GRIA2 or a GLRB/GRIA2 fusion gene leading to a protein with dominant-negative properties is causing the phenotype of the patient.

Interstitial 6q deletions can cause a variable phenotype depending on the size and location of the deletion. 6q14 deletions have been associated with intellectual disability and a distinct pattern of minor anomalies, including upslanted palpebral fissures with epicanthal folds, a short nose with broad nasal tip, anteverted nares, long philtrum, and thin upper lip. In this study we describe two patients with overlapping 6q14 deletions presenting with developmental delay and characteristic dysmorphism. Molecular karyotyping using array CGH analysis revealed a de novo 8.9 Mb deletion at 6q14.1-q14.3 and a de novo 11.3 Mb deletion at 6q12.1-6q14.1, respectively. We provide a review of the clinical features of twelve other patients with 6q14 deletions detected by array CGH analysis. By assessing all reported data we could not identify a single common region of deletion. Possible candidate genes in 6q14 for intellectual disability might be FILIP1, MYO6, HTR1B, and SNX14., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability., Methods: 99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced., Results: By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation., Conclusions: We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene., (© 2011 Gregor et al; licensee BioMed Central Ltd.)

In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]