[Show abstract][Hide abstract] ABSTRACT: Recently, de novo mutations in TBL1XR1 were found in two patients with autism spectrum disorders. Here, we report on a Japanese girl presenting with West syndrome, Rett syndrome-like and autistic features. Her initial development was normal until she developed a series of spasms at 5 months of age. Electroencephalogram at 7 months showed a pattern of hypsarrhythmia, which led to a diagnosis of West syndrome. Stereotypic hand movements appeared at 8 months of age, and autistic features such as deficits in communication, hyperactivity and excitability were observed later, at 4 years and 9 months. Whole exome sequencing of the patient and her parents revealed a de novo TBL1XR1 mutation [c.209 G>A (p.Gly70Asp)] occurring at an evolutionarily conserved amino acid in an F-box-like domain. Our report expands the clinical spectrum of TBL1XR1 mutations to West syndrome with Rett-like features, together with autistic features.Journal of Human Genetics advance online publication, 7 August 2014; doi:10.1038/jhg.2014.71.
[Show abstract][Hide abstract] ABSTRACT: We report on a 1-year-old boy with microcephaly with a simplified gyral pattern, early-onset seizures, congenital hearing loss and a severe developmental delay. Trio-based whole-exome sequencing identified candidate compound heterozygous mutations in two genes: c.163G>T (p.Ala55Ser) and c.874G>A (p.Gly292Arg) in polynucleotide kinase 3'-phosphatase gene (PNKP), and c.195G>A (p.Met65Ile) and c.1210A>C (p.Ser404Arg) in PCDH15. PNKP and PCDH15 mutations have been reported in autosomal recessive microcephaly with early-onset seizures and developmental delay syndrome, and Usher syndrome type 1F, respectively. Our patient showed neurological features similar to reported cases of both syndromes that could be explained by the observed mutations in both PNKP and PCDH15, which therefore appear to be pathogenic in this case.Journal of Human Genetics advance online publication, 26 June 2014; doi:10.1038/jhg.2014.51.
[Show abstract][Hide abstract] ABSTRACT: Iris hypoplasia (IH) is rare autosomal dominant disorder characterized by a poorly developed iris stroma and malformations of the eyes and umbilicus. This disorder is caused by mutation of the paired-like homeodomain 2 (PITX2) gene. Here, we describe a novel PITX2 mutation (c.205C4T) in an IH family presenting with very mild eye features but with tooth agenesis as the most obvious clinical feature. Human Genome Variation (2014) 1, 14005; doi:10.1038/hgv.2014.5; published online 31 July 2014 Mutations in the PITX2 (paired-like homeodomain 2) gene are associated with three allelic disorders: iris hypoplasia (IH), iridogoniodysgenesis syndrome (IGDS; OMIM 137600) and Axenfeld-Rieger syndrome (ARS; OMIM 180500). 1–3 Various dental abnormalities including tooth agenesis are also found in IH, IGDS and ARS, which are characterized by abnormal development of the anterior segment of the eyes and umbilicus anomalies. 1–4 IH shows the mildest phenotype among the three, characterized by only iris hypoplasia and glaucoma. 1,5 IGDS presents with goniodysgenesis in addition to iris hypoplasia and glaucoma. 2
[Show abstract][Hide abstract] ABSTRACT: Recessive mutations in genes of the glycosylphosphatidylinositol (GPI)-anchor synthesis pathway have been demonstrated as causative of GPI deficiency disorders associated with intellectual disability, seizures, and diverse congenital anomalies. We performed whole exome sequencing in a patient with progressive encephalopathies and multiple dysmorphism with hypophosphatasia and identified novel compound heterozygous mutations, c.250G>T (p. Glu84*) and c.1342C>T (p. Arg488Trp), in PIGT encoding a subunit of the GPI transamidase complex. The surface expression of GPI-anchored proteins (GPI-APs) on patient granulocytes was lower than that of healthy controls. Transfection of the Arg488Trp mutant PIGT construct, but not the Glu84* mutant, into PIGT-deficient cells partially restored the expression of GPI-APs DAF and CD59. These results indicate that PIGT mutations caused neurological impairment and multiple congenital anomalies in this patient.
[Show abstract][Hide abstract] ABSTRACT: We performed whole-exome sequencing analysis of patients with genetically unsolved hypomyelinating leukoencephalopathies, identifying 8 patients with TUBB4A mutations and allowing the phenotypic spectrum of TUBB4A mutations to be investigated.METHODS: Fourteen patients with hypomyelinating leukoencephalopathies, 7 clinically diagnosed with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and 7 with unclassified hypomyelinating leukoencephalopathy, were analyzed by whole-exome sequencing. The effect of the mutations on microtubule assembly was examined by mapping altered amino acids onto 3-dimensional models of the αβ-tubulin heterodimer.RESULTS: Six heterozygous missense mutations in TUBB4A, 5 of which are novel, were identified in 8 patients (6/7 patients with H-ABC [the remaining patient is an atypical case] and 2/7 patients with unclassified hypomyelinating leukoencephalopathy). In 4 cases with parental samples available, the mutations occurred de novo. Analysis of 3-dimensional models revealed that the p.Glu410Lys mutation, identified in patients with unclassified hypomyelinating leukoencephalopathy, directly impairs motor protein and/or microtubule-associated protein interactions with microtubules, whereas the other mutations affect longitudinal interactions for maintaining αβ-tubulin structure, suggesting different mechanisms in tubulin function impairment. In patients with the p.Glu410Lys mutation, basal ganglia atrophy was unobserved or minimal although extrapyramidal features were detected, suggesting its functional impairment.CONCLUSIONS: TUBB4A mutations cause typical H-ABC. Furthermore, TUBB4A mutations associate cases of unclassified hypomyelinating leukoencephalopathies with morphologically retained but functionally impaired basal ganglia, suggesting that TUBB4A-related hypomyelinating leukoencephalopathies encompass a broader clinical spectrum than previously expected. Extrapyramidal findings may be a key for consideration of TUBB4A mutations in hypomyelinating leukoencephalopathies.
[Show abstract][Hide abstract] ABSTRACT: Objective
De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs).MethodsA total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples).ResultsWe identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic–clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability.SignificanceOur data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
[Show abstract][Hide abstract] ABSTRACT: When an expected mutation in a particular disease-causing gene is not identified in a suspected carrier, it is usually assumed to be due to germline mosaicism. We report here very-low-grade somatic mosaicism in ACTA1 in an unaffected mother of two siblings affected with a neonatal form of nemaline myopathy. The mosaicism was detected by deep resequencing using a next-generation sequencer. We identified a novel heterozygous mutation in ACTA1, c.448A>G (p.Thr150Ala), in the affected siblings. Three-dimensional structural modeling suggested that this mutation may affect polymerization and/or actin's interactions with other proteins. In this family, we expected autosomal dominant inheritance with either parent demonstrating germline or somatic mosaicism. Sanger sequencing identified no mutation. However, further deep resequencing of this mutation on a next-generation sequencer identified very-low-grade somatic mosaicism in the mother: 0.4%, 1.1%, and 8.3% in the saliva, blood leukocytes, and nails, respectively. Our study demonstrates the possibility of very-low-grade somatic mosaicism in suspected carriers, rather than germline mosaicism.
[Show abstract][Hide abstract] ABSTRACT: To investigate the clinical spectrum caused by mutations in PIGA at Xp22.2, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, among patients with early-onset epileptic encephalopathies (EOEEs).
Whole-exome sequencing was performed as a comprehensive genetic analysis for a cohort of 172 patients with EOEEs including early myoclonic encephalopathy, Ohtahara syndrome, and West syndrome, and PIGA mutations were carefully investigated.
We identified 4 PIGA mutations in probands showing early myoclonic encephalopathy, West syndrome, or unclassified EOEE. Flow cytometry of blood granulocytes from patients demonstrated reduced expression of GPI-anchored proteins. Expression of GPI-anchored proteins in PIGA-deficient JY5 cells was only partially or hardly restored by transient expression of PIGA mutants with a weak TATA box promoter, indicating a variable loss of PIGA activity. The phenotypic consequences of PIGA mutations can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations. Severe forms involved myoclonus and asymmetrical suppression bursts on EEG, multiple anomalies with a dysmorphic face, and delayed myelination with restricted diffusion patterns in specific areas. The less severe form presented with intellectual disability and treatable seizures without facial dysmorphism.
Our study confirmed that PIGA mutations are one genetic cause of EOEE, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE.
[Show abstract][Hide abstract] ABSTRACT: The conserved oligomeric Golgi (COG) complex is involved in intra-Golgi retrograde trafficking, and mutations in six of its eight subunits have been reported in congenital disorders of glycosylation (CDG). Here we report a patient showing severe acquired microcephaly, psychomotor retardation, seizures, liver dysfunction, hypocupremia, and hypoceruloplasminemia. Analysis of his serum glycoproteins revealed defects in both sialylation and galactosylation of glycan termini. Trio-based whole-exome sequencing identified two heterozygous mutations in COG2: a de novo frameshift mutation [c.701dup (p.Tyr234*)] and a missense mutation [c.1900T>G (p.Trp634Gly)]. Sequencing of cloned reverse-transcription polymerase chain reaction products revealed that both mutations were located on separate alleles, as expected, and that the mutant transcript harboring the frameshift mutation underwent degradation. The c.1900T>G (p.Trp634Gly) mutation is located in a domain highly conserved among vertebrates and was absent from both the public database and our control exomes. Protein expression of COG2, along with COG3 and COG4, was decreased in fibroblasts from the patient. Our data strongly suggest that these compound heterozygous mutations in COG2 are causative of CDG.
[Show abstract][Hide abstract] ABSTRACT: Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by MECP2 mutations. We identified a de novo WDR45 mutation, which caused a subtype of neurodegeneration with brain iron accumulation, in a patient showing clinically typical RTT. The mutation (c.830+1G>A) led to aberrant splicing in lymphoblastoid cells. Sequential brain magnetic resonance imaging demonstrated that iron deposition in the globus pallidus and the substantia nigra was observed as early as at 11 years of age. Because the patient showed four of the main RTT diagnostic criteria, WDR45 should be investigated in patients with RTT without MECP2 mutations.Journal of Human Genetics advance online publication, 13 March 2014; doi:10.1038/jhg.2014.18.
Journal of Human Genetics 03/2014; · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eukaryotic elongation factor 1, alpha-2 (eEF1A2) protein is involved in protein synthesis, suppression of apoptosis, and regulation of actin function and cytoskeletal structure. EEF1A2 gene is highly expressed in the central nervous system and Eef1a2 knockout mice show the neuronal degeneration. Until now, only one missense mutation (c.208G>A, p.Gly70Ser) in EEF1A2 has been reported in two independent patients with neurological disease. In this report, we described two patients with de novo mutations (c.754G>C, p.Asp252His and c.364G>A, p.Glu122Lys) in EEF1A2 found by whole exome sequencing. Common clinical features are shared by all four individuals: severe intellectual disability, autistic behavior, absent speech, neonatal hypotonia, epilepsy and progressive microcephaly. Furthermore, the two patients share the similar characteristic facial features including a depressed nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth. These data strongly indicate that a new recognizable disorder is caused by EEF1A2 mutations.
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial diseases are associated with defects of adenosine triphosphate production and energy supply to organs as a result of dysfunctions of the mitochondrial respiratory chain. Biallelic mutations in the YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase cause myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2), a type of mitochondrial disease. Here, we report a consanguineous Turkish family with two siblings showing severe metabolic decompensation including recurrent hypoglycemia, lactic acidosis, and transfusion-dependent anemia. Using whole-exome sequencing of the proband and his parents, we identified a novel YARS2 mutation (c.1303A>G, p.Ser435Gly) that was homozygous in the patient and heterozygous in his parents. This mutation is located at the ribosomal protein S4-like domain of the gene, while other reported YARS2 mutations are all within the catalytic domain. Interestingly, the proband showed more severe symptoms and an earlier onset than previously reported patients, suggesting the functional importance of the S4-like domain in tyrosyl-tRNA synthetase.Journal of Human Genetics advance online publication, 16 January 2014; doi:10.1038/jhg.2013.143.
Journal of Human Genetics 01/2014; · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aberrations in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway constitute a subclass of congenital disorders of glycosylation, and mutations in seven genes involved in this pathway have been identified. Among them, mutations in PIGV and PIGO, which are involved in the late stages of GPI-anchor synthesis, and PGAP2, which is involved in fatty-acid GPI-anchor remodeling, are all causative for hyperphosphatasia with mental retardation syndrome (HPMRS). Using whole exome sequencing, we identified novel compound heterozygous PIGO mutations (c.389C>A [p.Thr130Asn] and c.1288C>T [p.Gln430*]) in two siblings, one of them having epileptic encephalopathy. GPI-anchored proteins (CD16 and CD24) on blood granulocytes were slightly decreased compared with a control and his mother. Our patients lacked the characteristic features of HPMRS, such as facial dysmorphology (showing only a tented mouth) and hypoplasia of distal phalanges, and had only a mild elevation of serum alkaline phosphatase (ALP). Our findings therefore expand the clinical spectrum of GPI-anchor deficiencies involving PIGO mutations to include epileptic encephalopathy with mild elevation of ALP.