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To identify novel genes associated with intellectual disability (ID) in four unrelated families. Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A. Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay. Other clinical features included hypotonia, short stature, seizures, and behavior disorder. Characteristic features were appreciated in some individuals but not all; in some cases, features became more apparent with age. We demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioral abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals. These data indicate that biallelic loss-of-function variants in UBE4A cause a novel intellectual disability syndrome, suggesting that UBE4A enzyme activity is required for normal development and neurological function.

Abstract A previously healthy and developmentally normal 5-year-old boy from Saudi Arabia presented with a 3 mo history of abnormal behavior in the form of hyperactivity, decreased social engagement, episodic aggressiveness, decreased cognitive performance in school, inappropriate laughter and talking to himself, insomnia, tics and other stereotyped behaviors. His clinical neurological examination did not reveal any focal neurological deficits, but a prolonged electroencephalogram showed non-specific slowing over the right hemisphere. A diagnosis of encephalopathy was entertained, and he underwent testing for infectious, toxic, metabolic and mitochondrial disorders. Magnetic resonance imaging of the brain and cerebrospinal fluid studies were all normal. However, a comprehensive evaluation of paraneoplastic antibodies from cerebrospinal fluid demonstrated the presence of antibodies against the alpha-3 subunit of the neuronal nicotinic acetylcholine receptor, a finding also documented by tests from two different laboratories. An extensive diagnostic investigation that included a fludeoxyglucose-positron emission tomography scan for malignancies showed negative results. The patient was treated with plasmapheresis treatments (five exchanges) that resulted in a significant improvement in his clinical picture. Following his initial treatments, the patient continued to receive monthly infusions of intravenous immunoglobulin. An evaluation at 5.5 mo after initiation of first treatment revealed a considerable improvement of his behavior and language abilities. The patient returned to his school where he has performed satisfactorily. To our knowledge, this is the first report of a child who developed sub-acute cognitive and neurobehavioral regression in association with the presence of a serum antibody to a neuronal ganglionic nicotinic acetylcholine receptor and who improved after immunotherapy.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1 , VAMP1 , MCTP2 , and TBP ). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes ( ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1 ) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease ( AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most “negative” clinical exome tests are unsolved due to interpretation rather than technical limitations.

Purpose Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. Methods Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results We highlight 30 published candidate genes ( ACTL6B , ADAM22 , AGTPBP1 , APC , C12orf4 , C3orf17 (NEPRO) , CENPF , CNPY3 , COL27A1 , DMBX1 , FUT8 , GOLGA2 , KIAA0556 , LENG8 , MCIDAS , MTMR9 , MYH11 , QRSL1 , RUBCN , SLC25A42 , SLC9A1 , TBXT , TFG , THUMPD1 , TRAF3IP2 , UFC1 , UFM1 , WDR81 , XRCC2 , ZAK ) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes ( ABCA2 , ARL6IP1 , ATP8A2 , CDK9 , CNKSR1 , DGAT1 , DMXL2 , GEMIN4 , HCN2 , HCRT , MYO9A , PARS2 , PLOD3 , PREPL , SCLT1 , STX3 , TXNRD2 , WIPI2 ) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. Conclusions Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Purpose. To review the postoperative seizure outcomes of patients that underwent surgery for epilepsy at King Faisal Specialist Hospital & Research Centre (KFSHRC). Methods. A descriptive retrospective study for 502 patients operated on for medically intractable epilepsy between 1998 and 2012. The surgical outcome was measured using the ILAE criteria. Results. The epilepsy surgery outcome for temporal lobe epilepsy surgery (ILAE classes 1, 2, and 3) at 12, 36, and 60 months is 79.6%, 74.2%, and 67%, respectively. The favorable 12- and 36-month outcomes for frontal lobe epilepsy surgery are 62% and 52%, respectively. For both parietal and occipital epilepsy lobe surgeries the 12- and 36-month outcomes are 67%. For multilobar epilepsy surgery, the 12- and 36-month outcomes are 65% and 50%, respectively. The 12- and 36-month outcomes for functional hemispherectomy epilepsy surgery are 64.2% and 63%, respectively. According to histopathology diagnosis, mesiotemporal sclerosis (MTS) and benign CNS tumors had the best favorable outcome after surgery at 1 year (77.27% and 84.3%, resp.,) and 3 years (76% and 75%, resp.,). The least favorable seizure-free outcome after 3 years occurred in cases with dual pathology (66.6%). Thirty-four epilepsy patients with normal magnetic resonance imaging (MRI) brain scans were surgically treated. The first- and third-year epilepsy surgery outcome of 17 temporal lobe surgeries were (53%) and (47%) seizure-free, respectively. The first- and third-year epilepsy surgery outcomes of 15 extratemporal epilepsy surgeries were (47%) and (33%) seizure-free. Conclusion. The best outcomes are achieved with temporal epilepsy surgery, mesial temporal sclerosis, and benign CNS tumor. The worst outcomes are from multilobar surgery, dual pathology, and normal MRI.

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. variants reduce ribosome levels specifically in neural progenitor cells. Inappropriately low ribosome levels cause a transient delay in radial glia fate commitment.Reduced ribosome levels impair translation of a selected subset of mRNAs.Genetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes.