X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases

Deletion of YWHAE in a patient with periventricular heterotopias and pronounced corpus callosum hypoplasia

1468-6244 (Electronic) 0022-2593 (Linking) Journal Article Research Support, Non-U.S. Gov'tBACKGROUND: Malformations of cortical development are not rare and cause a wide spectrum of neurological diseases based on the affected region in the cerebral cortex. A significant proportion of these malformations could have a genetic basis. However, genetic studies are limited because most cases are sporadic and mendelian forms are rare. METHODS: In order to identify new genetic causes in patients presenting defects of cortical organisation, array based comparative genomic hybridisation was performed in a cohort of 100 sporadic cases with various types of cortical malformations in search for inframicroscopic chromosomal rearrangements. RESULTS: In one patient presenting with periventricular nodular heterotopias and pronounced corpus callosum hypoplasia, a small (400 kb) 17p13.3 deletion involving the YWHAE gene was identified. It is shown that YWHAE is the only brain expressed gene in the deleted region and that the other genes in the interval are unlikely to contribute to the brain malformation phenotype of this patient. CONCLUSION: Most 17p13.3 deletions reported to date are large, such as the deletions causing Miller-Dieker syndrome, and involve several genes implicated in various steps of brain development. Haploinsufficiency of the mouse orthologue of YWHAE causes a defect of neuronal migration. However, the human counterpart of this phenotype was not known. The case described here represents the smallest reported deletion involving the YWHAE gene and could represent the human counterpart of the abnormal cortical organisation phenotype presented by the Ywhae heterozygous knockout mouse

Novel Compound Heterozygous Mutations in TBC1D24 Cause Familial Malignant Migrating Partial Seizures of Infancy

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The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability

IF 3.636 (2017)International audienceIntroductionA large number of genes involved in autosomal recessive forms of intellectual disability (ID) were identified over the past few years through whole-exome sequencing (WES) or whole-genome sequencing in consanguineous families. Disease-associated variants in TRAPPC9 were reported in eight multiplex consanguineous sibships from different ethnic backgrounds, and led to the delineation of the phenotype. Affected patients have microcephaly, obesity, normal motor development, severe ID, and language impairment and brain anomalies.PatientsWe report six new patients recruited through a national collaborative network.ResultsIn the two patients heterozygous for a copy-number variation (CNV), the phenotype was clinically relevant with regard to the literature, which prompted to sequence the second allele, leading to identification of disease-associated variants in both. The third patient was homozygote for an intragenic TRAPPC9 CNV. The phenotype of the patients reported was concordant with the literature. Recent reports emphasized the role of CNVs in the etiology of rare recessive disorders.ConclusionThis study demonstrates that CNVs significantly contribute to the mutational spectrum of TRAPPC9 gene, and also confirms the interest of combining WES with CNV analysis to provide a molecular diagnosis to patients with rare Mendelian disorders

Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth

Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID family we reported in 2004. Three additional families with likely pathogenic KIAA2022 mutations were discovered within the frame of systematic parallel sequencing of familial cases of XLID or in the context of routine array-CGH evaluation of sporadic intellectual deficiency (ID) cases. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. This duplication decreased KIAA2022 mRNA level in patients' lymphocytes by 60%. Detailed clinical examination of all patients, including the two initially reported, indicated moderate-to-severe ID with autistic features, strabismus in all patients, with no specific dysmorphic features other than a round face in infancy and no structural brain abnormalities on magnetic resonance imaging (MRI). Interestingly, the patient with decreased KIAA2022 expression had only mild ID with severe language delay and repetitive behaviors falling in the range of an autism spectrum disorder (ASD). Since little is known about KIAA2022 function, we conducted morphometric studies in cultured rat hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function

An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome

Abdollahpour H, Alawi M, Kortüm F, et al. An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome. European Journal of Human Genetics. 2015;23(2):256-259.The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome