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Mutations in the α-1a Tubulin ( TUBA1A) gene have recently been found to cause cortical malformations resemblant of classical lissencephaly but with a specific combination of features. To date, TUBA1A mutations have been described in five patients and three foetuses. Our aims were to establish how common TUBA1A mutations are in patients with lissencephaly and to contribute to defining the phenotype associated with TUBA1A mutation. We performed mutation analysis in the TUBA1A gene in 46 patients with classical lissencephaly. In 44 of the patients, mutations in the LIS1 and/or DCX genes had previously been excluded; in 2 patients, mutation analysis was only performed in TUBA1A based on magnetic resonance imaging (MRI) findings. We identified three new mutations and one recurrent mutation in five patients with variable patterns of lissencephaly on brain MRI. Four of the five patients had congenital microcephaly, and all had dysgenesis of the corpus callosum and cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. We estimate the frequency of mutation in TUBA1A gene in patients with classical lissencephaly to be approximately 4%, and although not as common as mutations in the LIS1 or DCX genes, mutation analysis in TUBA1A should be included in the molecular genetic diagnosis of classical lissencephaly, particularly in patients with the combination of features highlighted in this paper. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA) in association with RNA exosome encoding mutations has only recently been recognized. Here, we present an infant (female) with an EXOSC5 mutation (c.230_232del p.Glu77del) associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA. At the age of four months, she presented with signs of septic illness, after which she developed TMA. A stool culture showed rotavirus as a potential trigger. The patient received eculizumab once, alongside supportive treatment, while awaiting diagnostic analysis of TMA, including genetic complement analysis, all of which were negative. Eculizumab was withdrawn and the patient's TMA recovered quickly. A review of the literature identified an additional four patients (age < 1 year) who developed TMA after a viral trigger in the presence of mutations in EXOSC3. The recurrence of TMA in one of these patients with an EXOSC3 mutation while on eculizumab treatment underscores the apparent lack of responsiveness to C5 inhibition. In conclusion, mutations in genes influencing the RNA exosome, like EXOSC3 and EXOSC5, characterized by neurodevelopment and neurodegenerative disorders could potentially lead to TMA in the absence of complement dysregulation. Hence, these patients were likely non-responsive to eculizumab. [ABSTRACT FROM AUTHOR]

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Background: Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder characterized primarily by an inability to perceive physical pain from birth, resulting in the accumulation of bruising, inflammation, and fractures that affect patient's life expectancy. CIP has different forms including CIP and CIPA. CIP with Anhidrosis (CIPA) is the most common type of CIP, which is caused mainly by mutations in NTRK1 and NGF genes, and is characterized by mental retardation and the inability to sweat (Anhidrosis). Because of high consanguinity rates in Palestine, this rare disease appears to have a higher frequency than in other communities. However, there were no systematic studies to address the genetic factors that cause CIP in the Palestinian community. Methods: In our study, we used Sanger and Whole exome sequencing to genotype members of five CIP-affected Palestinian families. Results: Our results confirm the presence of the founder c.1860-1861insT mutation in the NTRK1 gene of Palestinian Bedouin CIPA patients. Furthermore, one CIPA family carried a missense c.2170 G > A (G724 S) mutation in exon 16 of the NTRK1 gene. Finally, a novel nonsense c.901 A > T mutation (K301*) was detected in exon 7 of the SCN9A gene in CIP without anhidrosis family. Conclusions: Our study revealed three mutations that cause CIP and CIPA in the Palestinian community, which can help in improving the process of diagnosis and genetic counseling and establishing protocols for the diagnosis and follow-up for the affected individuals. This is especially important given that early diagnosis and medical care interference can prevent unpleasant CIP and CIPA complications. [ABSTRACT FROM AUTHOR]

Polymicrogyria (PMG) is a relatively common complex malformation with cortical development, characterized by an exorbitant number of abnormally tiny gyri separated by shallow sulci. It is a neuronal migration disorder. Familial cases of PMG and the manifestation of PMG in patients with chromosomal aberrations and mutations indicate their important role of genetics in this disorder. The highly stereotyped and well-conserved nature of the cortical folding pattern in humans is suggestive of the genetic regulation of the process. The chromosomal abnormalities observed in PMG include deletions, duplications, chromosomal rearrangements, and aneuploidies. Two of the most common deletions in PMG are 22q11.2 deletion and 1p36 deletion. Further, mutations in several genes such as GPR56, TUBB2B, SRPX2, PAX6, EOMES, WDR62, TUBA8, KIAA1279, and COL18A1 are known to be associated with PMG. Intriguingly, these genes are responsible only for a small number of cases of PMG. The protein products of these genes are implicated in diverse molecular and cellular functions. Taken together, PMG could be the result of the disruption of several biological pathways. Different modes of Mendelian inheritance and non-Mendelian inheritance are seen in PMG. We have suggested a gene panel that can be used for the detection of malformations of cortical development. [ABSTRACT FROM AUTHOR]

Meckel syndrome (MKS), also known as the Meckel–Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of the primary cilia during early embryogenesis. The diagnostic criteria are based on clinical variability and genetic heterogeneity. Mutations in the MKS1 gene constitute approximately 7% of all MKS cases. Herein, we present a non-consanguineous couple with three abnormal pregnancies as the fetuses showed MKS-related phenotypes of the central nervous system malformation and postaxial polydactyly. Whole-exome sequencing identified two novel heterozygous mutations of MKS1 : c.350C>A and c.1408-14A>G. The nonsense mutation c.350C>A produced a premature stop codon and induced the truncation of the MKS1 protein (p.S117*). Reverse-transcription polymerase chain reaction (RT-PCR) showed that c.1408-14A>G skipped exon 16 and encoded the mutant MKS1 p.E471Lfs*92. Functional studies showed that these two mutations disrupted the B9–C2 domain of the MKS1 protein and attenuated the interactions with B9D2, the essential component of the ciliary transition zone. The couple finally got a healthy baby through preimplantation genetic testing for monogenic disorder (PGT-M) with haplotype linkage analysis. Thus, this study expanded the mutation spectrum of MKS1 and elucidated the genetic heterogeneity of MKS1 in clinical cases. [ABSTRACT FROM AUTHOR]

Illustrating the molecular consequence of deleterious mutations is essential for bridging the gap between genotype and phenotype. In the cancer field, differential expression of the two alleles on heterozygous sites could directly reflect the effect of a mutation under certain trans environment. We retrieved transcriptomes of osteosarcoma and normal tissues in human and mouse. We defined tumor-specific heterozygous mutations with stringent criteria by considering sequencing depth and ancestral state. We calculated the relative expression of mutated alleles and normal alleles on the missense mutation sites in osteosarcoma. There is a conserved pattern that the mutated alleles have globally higher expression levels than the normal alleles in tumors. In the shared genes with missense mutations in both human and mouse, the relative expression of mutated alleles is highly correlated. Moreover, shared genes are functionally more important than unshared genes, and are enriched in oncogenes. The oncogenic role of mutations in oncogene KMT2A is experimentally verified. We systematically illustrate the deleterious effects of missense mutations by showing the over-expression of mutated alleles. We partially bridge the gap between genotype and phenotype by surmising that the over-expression of the mutated alleles might break the cellular equilibrium and lead to tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: Primary microcephaly (MCPH) is a congenital neurodevelopmental disorder manifesting as small brain and intellectual disability. It underlies isolated reduction of the cerebral cortex that is reminiscent of early hominids which makes it suitable model disease to study the hominin‐specific volumetric expansion of brain. Mutations in 25 genes have been reported to cause this disorder. Although majority of these genes were discovered in the Pakistani population, still a significant proportion of these families remains uninvestigated. Methods: We studied a cohort of 32 MCPH families from different regions of Pakistan. For disease gene identification, genome‐wide linkage analysis, Sanger sequencing, gene panel, and whole‐exome sequencing were performed. Results: By employing these techniques individually or in combination, we were able to discern relevant disease‐causing DNA variants. Collectively, 15 novel mutations were observed in five different MCPH genes; ASPM (10), WDR62 (1), CDK5RAP2 (1), STIL (2), and CEP135 (1). In addition, 16 known mutations were also verified. We reviewed the literature and documented the published mutations in six MCPH genes. Intriguingly, our cohort also revealed a recurrent mutation, c.7782_7783delGA;p.(Lys2595Serfs*6), of ASPM reported worldwide. Drawing from this collective data, we propose two founder mutations, ASPM:c.9557C>G;p.(Ser3186*) and CENPJ:c.18delC;p.(Ser7Profs*2), in the Pakistani population. Conclusions: We discovered novel DNA variants, impairing the function of genes indispensable to build a proper functioning brain. Our study expands the mutational spectra of known MCPH genes and also provides supporting evidence to the pathogenicity of previously reported mutations. These novel DNA variants will be helpful for the clinicians and geneticists for establishing reliable diagnostic strategies for MCPH families. [ABSTRACT FROM AUTHOR]

Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next‐generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families. By collecting clinical information on these families and comparing their phenotypes with previously reported patients, we further describe the clinical variability of ARID resulting from alterations in the EXOSC gene family, and emphasize the role of RNA processing dysregulation in ARID. [ABSTRACT FROM AUTHOR]

Monosialotetrahexosylganglioside (GM1) is a rare lysosomal storage disorder caused by the deficiency of beta-galactosidase (β-Gal) encoded by galactose beta 1 (GLB1). It is clinically characterized by developmental delay attributed to multifold accumulation of GM1 gangliosides in nerve cells. In this study, we present a case of infantile GM1 gangliosidosis in a consanguineous Pakistani family. The child was presented with developmental delay, hepatosplenomegaly and recurrent chest infections at 7.5 months of age. Radiological and biochemical investigations including magnetic resonance imaging (MRI), bone marrow biopsy and urine oligosaccharide analyses suggested lysosomal storage disorder. Significantly low levels of β-Gal enzyme confirmed the diagnosis of GM1 gangliosidosis. DNA sequencing of GLB1 identified a homozygous 2-bp deletion c.881-882delAT (p.Tyr294Terfs) in exon 8. In silico analysis supported the deleterious effect of the variant. This study extends GLB1 mutation spectrum and should benefit genetic counselling and prenatal diagnosis of the affected family. [ABSTRACT FROM AUTHOR]

The Cobalamin C deficiency (cblC), characterized with elevated methylmalonic acidemia and homocystinuria in plasma, is an inborn error of cobalamin metabolism. The late-onset cblC siblings patients were rarely reported. In this study, we analyzed the clinical presentations and treatment outcomes of late-onset cblC in Chinese sibling patients with neuropsychiatric presentations. The clinical data of four pairs of Chinese patients were retrospectively analyzed. Serum homocysteine, urine organic acids measurements, neuroimaging exams and gene analysis were carried out in all patents. Patients were reevaluated after treatments with cobalamin, folate, betaine, L-carnitine and compound vitamin B. The mean age at disease onset was 13.7 (range 2-19) years. The neuropsychiatric disturbances including cognitive decline (3/8), psychiatric disturbances (4/8), gait instability (2/8), lower extremity weakness and numbness (3/8) and thromboembolic events (1/8). Two patients suffered nephropathy. The mean serum homocysteine when patients were diagnosed was 109.4 (range 69.5-138) μM/L. The abnormal radioimaging included scoliosis by X-ray (5/6), cerebral atrophy (4/6) and spinal cord atrophy (3/6) by MRI scan. Three pairs of siblings showed heterozygous mutations of MMACHC gene including c.482G > A (4/6), c.354G > C (2/6), c.570insT (2/6), c.445_446del (2/6) and c.656_4658del (2/6). The other two siblings showed homozygous mutation with c.452A > G in MMACHC gene. After treatments, the psychiatric symptoms were obviously relieved in all the patients. In Chinese siblings with late-onset cblC, the main clinic manifestation and abnormal radioimaging were cognitive decline and cerebral atrophy respectively. The most common gene mutation was c.482G > A of MMACHC gene. The patients responded well to the treatments. [ABSTRACT FROM AUTHOR]

Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on 4 patients from 2 families diagnosed with PCH who died within the first month of life from respiratory insufficiency. Patients from 1 family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease‐segregating loss‐of‐function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46‐associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme. [ABSTRACT FROM AUTHOR]

Glycerophospholipids are the most abundant constituents of biological membranes in Trypanosoma brucei, which causes sleeping sickness in humans and nagana in cattle. They are essential cellular components that fulfill various important functions beyond their structural role in biological membranes such as in signal transduction, regulation of membrane trafficking or control of cell cycle progression. Our previous studies have established that the glycerol-3-phosphate acyltransferase TbGAT is dispensable for growth, viability, and ester lipid biosynthesis suggesting the existence of another initial acyltransferase(s). This work presents the characterization of the alternative, dihydroxyacetonephosphate acyltransferase TbDAT, which acylates primarily dihydroxyacetonephosphate and prefers palmitoyl-CoA as an acyl-CoA donor. TbDAT restores the viability of a yeast double null mutant that lacks glycerol-3-phosphate and dihydroxyacetonephosphate acyltransferase activities. A conditional null mutant of TbDAT in T. brucei procyclic form was created and characterized. TbDAT was important for survival during stationary phase and synthesis of ether lipids. In contrast, TbDAT was dispensable for normal growth. Our results show that in T. brucei procyclic forms i) TbDAT but not TbGAT is the physiologically relevant initial acyltransferase and ii) ether lipid precursors are primarily made by TbDAT. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV, features loss of pain sensation, decreased or absent sweating (anhidrosis), recurrent episodes of unexplained fever, self-mutilating behavior, and variable mental retardation. Mutations in neurotrophic receptor tyrosine kinase 1 (NTRK1) have been reported to be associated with CIPA. We identified four novel NTRK1 mutations in six Korean patients from four unrelated families. Of the four mutations, we demonstrated using a splicing assay that IVS14+3A>T causes aberrant splicing of NTRK1 mRNA, leading to introduction of a premature termination codon. An NTRK1 autophosphorylation assay showed that c.1786G>A (p.Asp596Asn) abolished autophosphorylation of NTRK1. In addition, Western blotting showed that c.704C>G (p.Ser235*) and c.2350_2363del (p.Leu784Serfs*79) blunted NTRK1 expression to undetectable levels. The four novel NTRK1 mutations we report here will expand the repertoire of NTRK1 mutations in CIPA patients, and further our understanding of CIPA pathogenesis. [ABSTRACT FROM AUTHOR]

Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most common genetic type of functional cobalamin (vitamin B) deficiency. This metabolic disease is characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypotonia) and variable extracentral nervous system involvement (failure to thrive, cardiovascular, renal, ocular) manifesting predominantly early in life, sometimes during gestation. To enhance awareness and understanding of renal disease associated with cblC defect, we studied biochemical, genetic, clinical, and histopathological data from 36 patients. Consistent clinical chemistry features of renal disease were intravascular hemolysis, hematuria, and proteinuria in all patients, with nephrotic-range proteinuria observed in three. Renal function ranged from normal to renal failure, with eight patients requiring (intermittent) dialysis. Two thirds were diagnosed with atypical (diarrhea-negative) hemolytic uremic syndrome (HUS). Renal histopathology analyses of biopsy samples from 16 patients revealed glomerular lesions typical of thrombotic microangiopathy (TMA). Treatment with hydroxycobalamin improved renal function in the majority, including three in whom dialysis could be withdrawn. Neurological sequelae were observed in 44 % and cardiopulmonary involvement in 39 % of patients, with half of the latter group demonstrating pulmonary hypertension. Mortality reached 100 % in untreated patients and 79 and 56 % in those with cardiopulmonary or neurological involvement, respectively. In all patients presenting with unclear intravascular hemolysis, hematuria, and proteinuria, cblC defect should be ruled out by determination of blood/plasma homocysteine levels and/or genetic testing, irrespective of actual renal function and neurological status, to ensure timely diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Centriolar satellites comprise cytoplasmic granules that are located around the centrosome. Their molecular identification was first reported more than a quarter of a century ago. These particles are not static in the cell but instead constantly move around the centrosome. Over the last decade, significant advances in their molecular compositions and biological functions have been achieved due to comprehensive proteomics and genomics, super-resolution microscopy analyses and elegant genetic manipulations. Centriolar satellites play pivotal roles in centrosome assembly and primary cilium formation through the delivery of centriolar/centrosomal components from the cytoplasm to the centrosome. Their importance is further underscored by the fact that mutations in genes encoding satellite components and regulators lead to various human disorders such as ciliopathies. Moreover, the most recent findings highlight dynamic structural remodelling in response to internal and external cues and unexpected positive feedback control that is exerted from the centrosome for centriolar satellite integrity. [ABSTRACT FROM AUTHOR]

L1CAM gene mutations cause neurodevelopmental disorders collectively termed L1 syndrome. Insufficient information about L1CAM variants complicates clinical prognosis, genetic diagnosis and genetic counseling. We combined clinical data, in silico effect predictions and functional analysis of four L1CAM variants, p.I37N, p.T38M, p.M172I and p.D202Y, located to the two N-terminal Ig-like domains present in five families with symptoms of L1 syndrome. Software tools predicted destabilizing effects of p. I37N and p. D202Y but results for p. T38M and p. M172I were inconsistent. Cell surface expression of mutant proteins L1-T38M, L1-M172I and L1-D202Y was normal. Conversely, L1-I37N accumulated in the endoplasmic reticulum (ER) and showed temperature-sensitive protein maturation suggesting that p. I37N induces protein misfolding. L1CAM-mediated cell-cell aggregation was severely impaired by L1CAM variants p. I37N, p. M172I and p. D202Y but was preserved by the variant p. T38M. Our experimental data indicate that protein misfolding and accumulation in the ER affect function of the L1CAM variant p. I37N whereas the variants p. M172I and p. D202Y impair homophilic interaction at the cell surface. [ABSTRACT FROM AUTHOR]

The phosphoinositide 3-kinase (PI3K) generated lipid signals, PtdIns(3,4,5)P3 and PtdIns(3,4)P2, are both required for the maximal activation of the serine/threonine kinase proto-oncogene Akt. The inositol polyphosphate 5-phosphatases (5-phosphatases) hydrolyse the 5-position phosphate from the inositol head group of PtdIns(3,4,5)P3 to yield PtdIns(3,4)P2. Extensive work has revealed several 5-phosphatases inhibit PI3K-driven Akt signalling, by decreasing PtdIns(3,4,5)P3 despite increasing cellular levels of PtdIns(3,4)P2. The roles that 5-phosphatases play in suppressing cell proliferation and transformation are slow to emerge; however, the 5-phosphatase PIPP [proline-rich inositol polyphosphate 5-phosphatase; inositol polyphosphate 5-phosphatase (INPP5J)] has recently been identified as a putative tumour suppressor in melanoma and breast cancer and SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase 1] inhibits haematopoietic cell proliferation. INPP5E regulates cilia stability and INPP5E mutations have been implicated ciliopathy syndromes. This review will examine 5-phosphatase regulation of PI3K/Akt signalling, focussing on the role PtdIns(3,4,5)P3 5-phosphatases play in developmental diseases and cancer. [ABSTRACT FROM AUTHOR]

Background In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog of the human KIAA0586 gene, which encodes a novel coiled-coil domain protein essential for primary ciliogenesis, suggesting that KIAA0586 can be associated with ciliopathy in human beings. Methods In our patients with ciliopathy (http://www. clinicaltrials.gov: NCT00068224), we have collected extensive clinical and neuroimaging data from affected individuals, and performed whole exome sequencing on DNA from affected individuals and their parents. We analysed gene expression on fibroblast cell line, and determined the effect of gene mutation on ciliogenesis in cells derived from patients. Results We identified biallelic mutations in the human TALPID3 ortholog, KIAA0586, in six children with findings of overlapping Jeune and Joubert syndromes. Fibroblasts cultured from one of the patients with Jeune-Joubert syndrome exhibited more severe cilia defects than fibroblasts from patients with only Joubert syndrome; this difference was reflected in KIAA0586 RNA expression levels. Rescue of the cilia defect with full-length wild type KIAA0586 indicated a causal link between cilia formation and KIAA0586 function. Conclusions Our results show that biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Furthermore, our results confirm that KIAA0586/TALPID3 is essential in cilia formation in human beings, expand the KIAA0586 phenotype to include features of Jeune syndrome and provide a pathogenetic connection between Joubert and Jeune syndromes, based on aberrant ciliogenesis. [ABSTRACT FROM AUTHOR]

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are two genetically heterogeneous retinal degenerative disorders. Despite the identification of a number of genes involved in LCA and RP, the genetic etiology remains unknown in many patients. In this study, we aimed to identify novel disease-causing genes of LCA and RP. Retinal capture sequencing was initially performed to screen mutations in known disease-causing genes in different cohorts of LCA and RP patients. For patients with negative results, we performed whole exome sequencing and applied a series of variant filtering strategies. Sanger sequencing was done to validate candidate causative IFT140 variants. Exome sequencing data analysis led to the identification of IFT140 variants in multiple unrelated non-syndromic LCA and RP cases. All the variants are extremely rare and predicted to be damaging. All the variants passed Sanger validation and segregation tests provided that the family members' DNA was available. The results expand the phenotype spectrum of IFT140 mutations to non-syndromic retinal degeneration, thus extending our understanding of intraflagellar transport and primary cilia biology in the retina. This work also improves the molecular diagnosis of retinal degenerative disease. [ABSTRACT FROM AUTHOR]

Background: Cobalamin C (CblC) defects are inherited autosomal recessive disorders of vitamin B12 metabolism due to mutations in the MMACHC gene. Renal manifestations include thrombotic microangiopathy (TMA), acute or chronic renal failure, tubulointerstitial nephritis, and proximal renal tubular acidosis. However, reports about glomerular pathologies are scarce. Case report: A 4-year-old boy presented with nephrotic syndrome, arterial hypertension, and chronic anemia but no signs of hemolysis. Renal biopsy showed TMA with ischemic glomerular collapse, foot process effacement, and tubulointerstitial fibrosis. Elevated serum levels of homocysteine suggested a cobalamin C disorder. This was confirmed by the identification of compound heterozygous mutations in the MMACHC gene. Initial therapy consisted of antihypertensive treatment including angiotensin converting enzyme inhibitor (ACEi) leading to blood pressure control and a significant reduction of proteinuria. After a definite diagnosis of CblC deficiency, hydroxocobalamin was introduced. Thereafter, homocysteine levels decreased, anemia resolved, and a further decline of proteinuria with normalization of serum protein levels was noted. Renal function remained stable. Conclusions: Although uncommon, the clinical picture of CblC defects may be ruled by nephrotic syndrome mimicking glomerulonephritis, minimal change disease, or primary focal and segmental glomerulosclerosis. Key to a correct diagnosis is elevated serum levels of homocysteine, and a definite diagnosis can be confirmed by genetic testing. [ABSTRACT FROM AUTHOR]

Mammalian muscle cell differentiation is a complex process of multiple steps for which many of the factors involved have not yet been defined. In a screen to identify the regulators of myogenic cell fusion, we found that the gene for G-protein coupled receptor 56 ( GPR56) was transiently up-regulated during the early fusion of human myoblasts. Human mutations in the gene for GPR56 cause the disease bilateral frontoparietal polymicrogyria; however, the consequences of receptor dysfunction on muscle development have not been explored. Using knockout mice, we defined the role of GPR56 in skeletal muscle. GPR56−/− myoblasts have decreased fusion and smaller myotube sizes in culture. In addition, a loss of GPR56 expression in muscle cells results in decreases or delays in the expression of myogenic differentiation 1, myogenin and nuclear factor of activated T-cell ( NFAT)c2. Our data suggest that these abnormalities result from decreased GPR56-mediated serum response element and NFAT signalling. Despite these changes, no overt differences in phenotype were identified in the muscle of GPR56 knockout mice, which presented only a mild but statistically significant elevation of serum creatine kinase compared to wild-type. In agreement with these findings, clinical data from 13 bilateral frontoparietal polymicrogyria patients revealed mild serum creatine kinase increase in only two patients. In summary, targeted disruption of GPR56 in mice results in myoblast abnormalities. The absence of a severe muscle phenotype in GPR56 knockout mice and human patients suggests that other factors may compensate for the lack of this G-protein coupled receptor during muscle development and that the motor delay observed in these patients is likely not a result of primary muscle abnormalities. [ABSTRACT FROM AUTHOR]

Pontocerebellar hypoplasia type 1 (PCH1) is characterized by cerebellar and anterior horn motor neuron degeneration and loss, signs of spinal muscular atrophy plus. Patients manifest severe perinatal weakness, hypotonia, and respiratory insufficiency, causing death frequently before the age of 1 year. Recently, causative mutations in EXOSC3 were reported in a majority of PCH1 patients, but the detailed clinical phenotype caused by EXOSC3 mutations, genotype-phenotype correlations, and prevalent mutations in specific ethnic groups is not yet known. Three unrelated Czech Roma patients with PCH1 were investigated clinically, electrophysiologically, neuroradiologically, and neuropathologically (patients 1 and 2). The entire coding region of the EXOSC3 gene, including the adjacent intron sequences, was sequenced in all three patients. The same mutation c.92G→C, p.G31A in EXOSC3 was found in all three affected patients in homozygous state and in heterozygous state in the parents from two of the families. Haplotype analysis with four flanking microsatellite markers showed identical haplotype in 9 out of 11 haplotypes carrying the c.92G→C, p.G31A mutation. Furthermore, four heterozygotes for this mutation were found in anonymous DNA samples from 90 unrelated Roma individuals. All four of these samples shared the same haplotype. No heterozygous sample was found among 120 anonymous DNA samples from Czech non-Roma individuals with no familial relation. It may therefore be concluded that EXOSC3 c.92G→C, p.G31A mutation is a founder mutation with high prevalence among the Czech Roma causing a similar and particularly severe phenotype of PCH1. These observations from the Czech Roma may have consequences also for other Roma from other countries. PCH1 caused by EXOSC3 founder mutation c.92G→C, p.G31A extends the list of autosomal recessive disorders rare among the general population but more frequent among Roma at least in the Czech Republic. [ABSTRACT FROM AUTHOR]

Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal-recessive cystic kidney diseases. More than 13 genes are implicated in its pathogenesis to date, accounting for only 40 % of all cases. High-throughput mutation screenings of large patient cohorts represent a powerful tool for diagnostics and identification of novel NPHP genes. We here performed a new high-throughput mutation analysis method to study 13 established NPHP genes ( NPHP1- NPHP13) in a worldwide cohort of 1,056 patients diagnosed with NPHP-RC. We first applied multiplexed PCR-based amplification using Fluidigm Access-Array™ technology followed by barcoding and next-generation resequencing on an Illumina platform. As a result, we established the molecular diagnosis in 127/1,056 independent individuals (12.0 %) and identified a single heterozygous truncating mutation in an additional 31 individuals (2.9 %). Altogether, we detected 159 different mutations in 11 out of 13 different NPHP genes, 99 of which were novel. Phenotypically most remarkable were two patients with truncating mutations in INVS/NPHP2 who did not present as infants and did not exhibit extrarenal manifestations. In addition, we present the first case of Caroli disease due to mutations in WDR19/NPHP13 and the second case ever with a recessive mutation in GLIS2/NPHP7. This study represents the most comprehensive mutation analysis in NPHP-RC patients, identifying the largest number of novel mutations in a single study worldwide. [ABSTRACT FROM AUTHOR]

Pontocerebellar hypoplasia (PCH) type 1 is characterized by the co-occurrence of spinal anterior horn involvement and hypoplasia of the cerebellum and pons. EXOSC3 has been recently defined as a major cause of PCH type 1. Three different phenotypes showing variable severity have been reported. We identified a homozygous mutation [c.395A > C/p.D132A] in EXOSC3 in four patients with muscle hypotonia, developmental delay, spinal anterior horn involvement, and prolonged survival, consistent with the 'mild PCH1 phenotype'. Interestingly, isolated cerebellar hypoplasia limited to the hemispheres or involving both hemispheres and vermis was the main neuroradiologic finding, whereas the pontine volume was in the normal range for age. These findings strongly suggest that analysis of the EXOSC3 gene should be recommended also in patients with spinal anterior horn involvement and isolated cerebellar hypoplasia. [ABSTRACT FROM AUTHOR]

Ciliopathies are a group of clinically and genetically overlapping disorders whose etiologies lie in defective cilia. These are antenna-like organelles on the apical surface of numerous cell types in a variety of tissues and organs, the kidney included. Cilia play essential roles during development and tissue homeostasis, and their dysfunction in the kidney has been associated with renal cyst formation and renal failure. Recently, the term 'renal ciliopathies' was coined for those human genetic disorders that are characterized by nephronophthisis, cystic kidneys or renal cystic dysplasia. This review focuses on renal ciliopathies from a human genetics perspective. We survey the newest insights with respect to gene identification and genotype-phenotype correlations, and we reflect on candidate ciliopathies. The opportunities and challenges of next-generation sequencing (NGS) for genetic renal research and clinical DNA diagnostics are also reviewed, and we discuss the contribution of NGS to the development of personalized therapy for patients with renal ciliopathies. [ABSTRACT FROM AUTHOR]

Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. Polymicrogyria has been associated with genetic and environmental causes and is considered a malformation secondary to abnormal post-migrational development. However, the aetiology in many individuals with these cortical malformations is still unknown. During the past few years, mutations in a number of neuron-specific α- and β-tubulin genes have been identified in both lissencephaly and polymicrogyria, usually associated with additional cerebral anomalies including callosal hypoplasia or agenesis, abnormal basal ganglia and cerebellar hypoplasia. The tubulin proteins form heterodimers that incorporate into microtubules, cytoskeletal structures essential for cell motility and function. In this study, we sequenced the TUBB2B and TUBA1A coding regions in 47 patients with a diagnosis of polymicrogyria and five with an atypical lissencephaly on neuroimaging. We identified four β-tubulin and two α-tubulin mutations in patients with a spectrum of cortical and extra-cortical anomalies. Dysmorphic basal ganglia with an abnormal internal capsule were the most consistent feature. One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in ‘classical’ polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins. [ABSTRACT FROM AUTHOR]

The infantile-onset axonal neuropathies and neuronopathies are an uncommon and heterogeneous group of conditions causing weakness, wasting, and developmental delay in early childhood. Many are associated with central nervous system or other systemic manifestations and cause early mortality. We review the axonal Charcot-Marie-Tooth subtypes with onset in infancy, spinal muscular atrophy, and related syndromes of early infancy, giant axonal neuropathy, infantile neuroaxonal dystrophy, hereditary motor and sensory neuropathy with agenesis of the corpus callosum, early-onset neuropathies associated with mitochondrial disorders, and other less well-delineated clinical entities. Useful clinical and neuropathologic features in the diagnostic work-up of these conditions are also presented. [ABSTRACT FROM AUTHOR]

Joubert syndrome and related diseases (JSRD) are cerebello-oculo-renal syndromes with phenotypes including cerebellar hypoplasia, retinal dystrophy, and nephronophthisis (a cystic kidney disease). Mutations in AHI1 are the most common genetic cause of JSRD, with developmental hindbrain anomalies and retinal degeneration being prominent features. We demonstrate that Ahi1, a WD40 domain-containing protein, is highly conserved throughout evolution and its expression associates with ciliated organisms. In zebrafish ahi1 morphants, the phenotypic spectrum of JSRD is modeled, with embryos showing brain, eye, and ear abnormalities, together with renal cysts and cloacal dilatation. Following ahi1 knockdown in zebrafish, we demonstrate loss of cilia at Kupffer's vesicle and subsequently defects in cardiac left-right asymmetry. Finally, using siRNA in renal epithelial cells we demonstrate a role for Ahi1 in both ciliogenesis and cell-cell junction formation. These data support a role for Ahi1 in epithelial cell organization and ciliary formation and explain the ciliopathy phenotype of AHI1 mutations in man. [ABSTRACT FROM AUTHOR]

Ciliopathies comprise a group of disorders associated with genetic mutations encoding defective proteins, which result in either abnormal formation or function of cilia. As cilia are a component of almost all vertebrate cells, cilia dysfunction can manifest as a constellation of features that include characteristically, retinal degeneration, renal disease and cerebral anomalies. Additional manifestations include congenital fibrocystic diseases of the liver, diabetes, obesity and skeletal dysplasias. Ciliopathic features have been associated with mutations in over 40 genes to date. However, with over 1,000 polypeptides currently identified within the ciliary proteome, several other disorders associated with this constellation of clinical features will likely be ascribed to mutations in other ciliary genes. The mechanisms underlying many of the disease phenotypes associated with ciliary dysfunction have yet to be fully elucidated. Several elegant studies have crucially demonstrated the dynamic ciliary localisation of components of the Hedgehog and Wnt signalling pathways during signal transduction. Given the critical role of the cilium in transducing 'outside-in' signals, it is not surprising therefore, that the disease phenotypes consequent to ciliary dysfunction are a manifestation of aberrant signal transduction. Further investigation is now needed to explore the developmental and physiological roles of aberrant signal transduction in the manifestation of ciliopathy phenotypes. Utilisation of conditional and inducible murine models to delete or overexpress individual ciliary genes in a spatiotemporal and organ/cell-specific manner should help clarify some of the functional roles of ciliary proteins in the manifestation of phenotypic features. [ABSTRACT FROM AUTHOR]

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and the most frequent genetic cause of end-stage renal disease up to the third decade of life. It is caused by mutations in 11 different genes, denoted nephrocystins ( NPHP1-11, NPHP1L). As an increasing number of these genes are identified, our knowledge of nephronophthisis is changing, thereby improving our understanding of the pathomechanisms in NPHP. Recent publications have described ciliary expression of nephrocystins together with other cystoproteins, such as polycystins 1 and 2 and fibrocystin. These findings have shifted our focus to a pathomechanism involving defects in ciliary function (ciliopathy) and planar cell polarity (PCP). In addition, discoveries of new nephrocystin genes have shown that the disease spectrum of NPHP is much broader than previously anticipated. Different forms of mutations within the same NPHP gene can cause different disease severity. In this review, we highlight the different hypotheses on the pathomechanisms for NPHP and underline the clinical variability of this disease. The clinical spectrum has become even more complex with the possibility of oligogenicity in NPHP. [ABSTRACT FROM AUTHOR]

The article presents information on a study conducted on the classification, diagnosis, and treatment of Pontocerebellar Hypoplasia (PCH), a neurodegenerative disorder. Till now, seven different subtypes of PCH have been reported; and all subtypes share common characteristics, including hypoplasia or atrophy of cerebellum, progressive microcephaly, and variable cerebral involvement. Mutations in three tRNA splicing endonuclease subunit genes were found to be responsible for PCH.

The list of genes that when mutated cause disruptions in cerebellar development is rapidly increasing. The study of both spontaneous and engineered mouse mutants has been essential to this progress, as it has revealed much of our current understanding of the developmental processes required to construct the mature cerebellum. Improvements in brain imaging, such as magnetic resonance imaging (MRI) and the emergence of better classification schemes for human cerebellar malformations, have recently led to the identification of a number of genes which cause human cerebellar disorders. In this review we argue that synergistic approaches combining classical molecular techniques, genomics, and mouse models of human malformations will be essential to fuel additional discoveries of cerebellar developmental genes and mechanisms. [ABSTRACT FROM AUTHOR]

The plasma membrane phosphoinositide phosphatidylinositol 4,5-bisphosphate (PIP2) controls the activity of most ion channels tested thus far through direct electrostatic interactions. Mutations in channel proteins that change their apparent affinity to PIP2 can lead to channelopathies. Given the fundamental role that membrane phosphoinositides play in regulating channel activity, it is surprising that only a small number of channelopathies have been linked to phosphoinositides. This review proposes that for channels whose activity is PIP2-dependent and for which mutations can lead to channelopathies, the possibility that the mutations alter channel-PIP2 interactions ought to be tested. Similarly, diseases that are linked to disorders of the phosphoinositide pathway result in altered PIP2 levels. In such cases, it is proposed that the possibility for a concomitant dysregulation of channel activity also ought to be tested. The ever-growing list of ion channels whose activity depends on interactions with PIP2 promises to provide a mechanism by which defects on either the channel protein or the phosphoinositide levels can lead to disease. [ABSTRACT FROM AUTHOR]

We report the clinical characteristics and the outcome of two cases of pontocerebellar hypoplasia (PCH) in one family. The objective of this report is to describe the mode of presentation, discuss the clinical course, and address the dilemma of prenatal diagnosis and the prospects for genetic diagnosis for PCH. The first case is a 4-year-old boy in whom the diagnosis was made in the neonatal period. Despite extensive prenatal follow-up during the mother's subsequent pregnancy, prenatal diagnosis could not be made and a second affected child was born. Both siblings have severe developmental delay. The cases raise an important ethical dilemma about the most appropriate intervention if the mother of a child affected with PCH becomes pregnant. PCH is considered to have an autosomal-recessive mode of inheritance and a recurrence risk of 25% in each pregnancy. Until recently when genetic mutations in PCH types 2, 4, and 6 began to be identified, the lack of well-recognized genetic testing precluded experts from making clear recommendations. The best advice to these parents was difficult or elusive. With two children currently affected, should the parents terminate or continue with the latest pregnancy? Extensive monitoring with serial prenatal ultrasound failed in the previous pregnancy and resulted in the birth of the second affected child. It is evident that serial ultrasound scan may not be helpful in making the diagnosis prenatally. Therefore, other diagnostic modalities such as magnetic resonance imaging may be necessary and should be considered. With the identification of genetic basis or mutations in PCH types 2, 4, and 6 and possible development of commercial genetic testing for these types of PCH, reproductive decision or genetic testing during pregnancy should be recommended to affected families to enable informed choices. [ABSTRACT FROM AUTHOR]

Joubert Syndrome (JS) is an inherited ciliopathy associated with mutations in genes essential in primary cilium function. Whole exome sequencing in a multiplex consanguineous family from India revealed a KIAA0556 homozygous single base pair deletion mutation (c.4420del; p.Met1474Cysfs*11). Knockdown of the gene in zebrafish resulted in a ciliopathy phenotype, rescued by co-injection of wildtype cDNA. Affected siblings present a mild and classical form of Joubert syndrome allowing for further delineation of the JS associated genotypic spectrum. [ABSTRACT FROM AUTHOR]

Primary cilia are sensory organelles that protrude from the surface of most mammalian cell types. In humans and mice, mutations in proteins required for normal cilia function have been identified as causing a class of disorders with overlapping phenotypes known as ciliopathies. Recent evidence has linked obesity in ciliopathies to both the regulation of energy homeostasis in the hypothalamus and to adipogenesis. This article considers the role of cilia in these processes and whether cilia dysfunction may be relevant to more common forms of obesity. [ABSTRACT FROM AUTHOR]

Bilateral frontoparietal polymicrogyria (BFPP) has been reported in sporadic patients and in recessive pedigrees. Eleven mutations in GPR56, a gene encoding an evolutionarily dynamic G-protein–coupled receptor, have been identified in 29 patients from 18 families. The clinical features of BFPP include severe mental retardation, motor and language impairment, and epilepsy. No detailed description of the epilepsy is available for the patients reported to date. We report three consanguineous families in which four affected individuals with BFPP and GPR56 mutations had Lennox-Gastaut syndrome. Family studies, brain magnetic resonance imaging (MRI), electroencephalography (EEG)-video recordings, and mutation analysis. In Family 1, with one affected proband, we found an R565W change in the second extracellular loop of GPR56, involving a highly conserved aminoacidic residue. In Family 2, with one affected proband, we found an R79X change affecting the protein N-terminus and predicted to cause a premature truncation with loss of the G-protein–coupled receptor proteolytic site. In family 3, with two affected siblings, we found an R33P substitution in the protein N-terminus, involving a highly conserved aminoacidic residue. Epilepsy, present in all four patients, had started between ages 1 and 8 years, with infantile spasms in one patient and with de novo Lennox-Gastaut syndrome in the remaining three. All patients had Lennox-Gastaut syndrome when last observed, at ages 13 to 32 years. Several genes, when mutated, can cause malformations of cortical development that have been associated with the Lennox-Gastaut syndrome. BFPP caused by GPR56 mutations represents an additional , although rare, genetically determined cause of Lennox-Gastaut syndrome. [ABSTRACT FROM AUTHOR]

Cerebral giantism or Sotos syndrome consists of a pre- and postnatal overgrowth whose genetic basis are mutations and deletions of the nuclear receptor-binding SET domain containing protein gene. These patients have an increased risk of developing neoplasms, especially in adulthood. We report a 9-year-old boy, diagnosed with familial Sotos syndrome, who had two pilomatrixoma, symmetrically located on both sides of the neck, measuring 4 cm in diameter. Genetic study of the tumor tissue showed deletion of exon 22 of the NSD1 gene, whereas β-catenin gene mutations were not detected. To the best of our knowledge, presentation of multiple pilomatricomas with Sotos syndrome has never been reported. Therefore their association probably is incidental. Nevertheless, the unusual size of our patient’s pilomatricomas could be due to deletion of the NSD1 gene, which characterizes Sotos syndrome. [ABSTRACT FROM AUTHOR]

The malformations of the cerebral cortex represent a major cause of developmental disabilities, severe epilepsy and reproductive disadvantage. The advent of high-resolution MRI techniques has facilitated the in vivo identification of a large group of cortical malformation phenotypes. Several malformation syndromes caused by abnormal cortical development have been recognised and specific causative gene defects have been identified. Periventricular nodular heterotopia (PNH) is a malformation of neuronal migration in which a subset of neurons fails to migrate into the developing cerebral cortex. X-linked PNH is mainly seen in females and is often associated with focal epilepsy. FLNA mutations have been reported in all familial cases and in about 25% of sporadic patients. A rare recessive form of PNH due ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay and early seizures. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) are disorders of neuronal migration and represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior SBH owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Mutations of DCX have also been found in male patients with anterior SBH and in female relatives with normal brain magnetic resonance imaging. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin ( RELN) gene. X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene. Affected boys have severe delay and seizures with suppression-burst EEG. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dominant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy. Recessive bilateral frontoparietal polymicrogyria has been associated with mutations of the GPR56 gene. Epilepsy is often present in patients with cortical malformations and tends to be severe, although its incidence and type vary in different malformations. It is estimated that up to 40% of children with drug-resistant epilepsy have a cortical malformation. However, the physiopathological mechanisms relating cortical malformations to epilepsy remain elusive. [ABSTRACT FROM AUTHOR]

Molecular analysis of five Brazilian families, including eight patients presenting with nonclassic Tay-Sachs disease, was performed to identify frequent causative mutations and their correlation with clinical course. Three patients were affected by the B1 subacute variant and were shown to carry the R178H mutation (the DN allele), which is also common among Portuguese patients. Two of them were compound heterozygotes, whereas the third presented with the mutation in both alleles. Since Brazil was a Portuguese colony for over two centuries, common ancestry might be the probable explanation. The fourth patient presented with a juvenile phenotype and carries the R499H mutation, which has been reported only once worldwide and is associated with residual enzyme activity, responsible for a slower clinical course. The fifth family, of an Ashkenazi Jewish background, showed an extensive intrafamilial clinical variability among three affected sibs presenting with muscle atrophy, ataxia, and psychiatric symptoms. They were first diagnosed as having atypical spinal muscular atrophy and, subsequently, spinocerebellar ataxia, but, recently, the diagnosis of lateonset Tay-Sachs disease was confirmed based on reduced plasma hexosaminidase A activity and the G269S/InsTATC1278 genotype. It is therefore highly recommended to test patients with a similar clinical history for Tay-Sachs disease. In the same family, one first cousin committed suicide at the age of 24 years, presenting with a clinical phenotype that suggested an undiagnosed case and highlighting the effect of the intrafamilial clinical variability in delaying a prompt diagnosis. It is now recognized that his parents are, in fact, a carrier couple. Additionally, another relative had been previously identified as a heterozygote in a Tay-Sachs disease screening program, but the information was not shared among the family. Since this information might anticipate diagnosis and genetic counseling, it is advisable that heterozygote screening programs encourage families to share genetic information. [ABSTRACT FROM AUTHOR]

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1,000 male births. It is a complex disorder associated with genetic and environmental factors and can be part of genetic syndromes. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation. It is caused by mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1). To date, 68 deletion/mutation-positive cases have been reported. Genitourinary anomalies are common in MWS. Here we report that hypospadias is common in males with this syndrome. In 39 patients where this information was available, hypospadias was present in 46% of patients (18/39). In the 3 Italian male cases reported here, hypospadias was always present. MWS should be considered by endocrinologists in patients with hypospadias associated with developmental delays/mental retardation, in particular in the presence of a distinct facial phenotype. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We reviewed the epileptogenic cortical malformations for which a causative gene has been cloned or a linkage obtained. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with epilepsy in female patients and prenatal lethality in most males. About 90% of patients have focal epilepsy. Filamin A mutations have been reported in all families and in∼20% of sporadic patients. A rare recessive form of BPNH also has been reported. Most cases of lissencephaly–pachygyria are caused by mutations ofLIS1andXLISgenes.LIS1mutations cause a more severe malformation posteriorly. Most children have isolated lissencephaly, with severe developmental delay and infantile spasms, but milder phenotypes have been recorded.XLISusually causes anteriorly predominant lissencephaly in male patients and subcortical band heterotopia (SBH) in female patients. Thickness of the band and severity of pachygyria correlate with the likelihood of developing Lennox–Gastaut syndrome. Mutations of the coding region ofXLISare found in all reported pedigrees and in 50% of sporadic female patients with SBH. Autosomal recessive lissencephaly with cerebellar hypoplasia; accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the RELN gene. Schizencephaly has a wide anatomoclinical spectrum, including focal epilepsy in most patients. Familial occurrence is rare. Initial reports of heterozygous mutations in theEMX2gene need confirmation. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to Xq28 in some pedigrees, autosomal recessive inheritance in others, and association with 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy, often Lennox–Gastaut syndrome. Recessive bilateral frontal polymicrogyria has been linked to chromosome 16q12.2–21. [ABSTRACT FROM AUTHOR]

Uniparental disomy (UPD) is defined as the presence of a chromosome pair that derives from only one parent in a diploid individual. The human TRKA gene on chromosome 1q21-q22 encodes a receptor tyrosine kinase for nerve growth factor and is responsible for an autosomal recessive genetic disorder: congenital insensitivity to pain with anhidrosis (CIPA). We report here the second case of paternal UPD for chromosome 1 in a male patient with CIPA who developed normally at term and did not show overt dysmorphisms or malformations. He had only the usual features of CIPA with a homozygous mutation at the TRKA locus and a normal karyotype with no visible deletions or evidence of monosomy 1. Haplotype analysis of the TRKA locus and allelotype analyses of whole chromosome 1 revealed that the chromosome pair was exclusively derived from his father. Non-maternity was excluded by analyses of autosomes other than chromosome 1. Thus, we have identified a complete paternal isodisomy for chromosome 1 as the cause of reduction to homozygosity of the TRKA gene mutation, leading to CIPA. Our findings further support the idea that there are no paternally imprinted genes on chromosome 1 with a major effect on phenotype. UPD must be considered as a rare but possible cause of autosomal recessive disorders when conducting genetic testing. [ABSTRACT FROM AUTHOR]

The human TRKA gene encodes a high-affinity tyrosine kinase receptor for nerve growth factor. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder reported from various countries and characterized by anhidrosis (inability to sweat), the absence of reaction to noxious stimuli, and mental retardation. We have found that TRKA is the gene responsible for CIPA. We have studied TRKA in 46 CIPA chromosomes derived from 23 unrelated Japanese CIPA families, including three that have been previously reported, and identified 11 novel mutations. Four (L93P, G516R, R648 C, and D668Y) are missense mutations that result in amino acid substitutions at positions conserved in the TRK family, including TRKA, TRKB, and TRKC. Three (S131 fs, L579 fs, and D770 fs) are frameshift mutations. Three (E164X, Y359X, and R596X) are nonsense mutations. The other is an intronic branch-site (IVS7–33T→A) mutation, causing aberrant splicing in vitro. We also report the characterization of eight intragenic polymorphic sites, including a variable dinucleotide repeat and seven single nucleotide polymorphisms, and describe the haplotypic associations of alleles at these sites in 106 normal chromosomes and 46 CIPA chromosomes. More than 50% of CIPA chromosomes share the frameshift mutation (R548 fs) that we described earlier. This mutation apparently shows linkage disequilibrium with a rare haplotype in normal chromosomes, strongly suggesting that it is a common founder mutation. These findings represent the first extensive analysis of CIPA mutations and associated intragenic polymorphisms; they should facilitate the detection of CIPA mutations and aid in the diagnosis and genetic counseling of this painless but severe genetic disorder with devastating complications. [ABSTRACT FROM AUTHOR]

Type 2 congenital microcephaly (MCPH2) is a brain development disorder characterized by primary microcephaly with or without brain malformations. MCPH2 is caused by mutations in the WDR62 gene. We present three new patients with MCPH2 and compound heterozygous mutations in the WDR62 gene. In all the cases, the parents were healthy and unrelated. All children were clinically diagnosed with congenital microcephaly and retardation of motor and speech development. Sequencing results in the presented patients revealed five new variants in the WDR62 gene (c.4273C>T, c.1711_1712insTA, c.1777_1778delGA, c.1642+2T>G, c.194T>A) and one previously described in the German population (c.2864_2867delACAG). In two of the presented cases, variants in the SMAD4, DKC1, and ATRX genes were also found with unknown effects on the course of the disease. Moreover, in the article we collected and compared the most common clinical symptoms, dysmorphic features, and changes in radiographic examinations of the brain observed in 120 patients with recessive primary microcephaly type 2 caused by mutations in the WDR62 gene. [ABSTRACT FROM AUTHOR]

The article presents a case study of two siblings, a 21-year-old man and 27-year old man, who were presented with juvenile amyotrophic lateral sclerosis (ALS2). It states that signs of lower motor neuron involvement was shown in the electromyographic examination. It says that all cases with an early onset motor neuron disease should be suspected with ALS2 gene mutations.

The article presents information on polymicrogyria and epilepsy. It is stated that polymicrogyria is a common cortical malformation and is associated with mutations of only a few genes including SRPX2, PAX6 TBR2 and KIAA1279. It mentions that syndromes of regional polymicrogyria include bilateral perisylvian polymicrogyria, bilateral frontal and frontoparietal polymicrogyria. It is also stated that polymicrogyria has been linked to a spectrum of epilepsy phenotypes.

Background Cohen syndrome is a rare autosomal recessive inherited disorder that results from mutations of the VPS13B gene. Clinical features consist of a combination of mental retardation, facial dysmorphism, postnatal microcephaly, truncal obesity, slender extremities, joint hyperextensibility, myopia, progressive chorioretinal dystrophy, and intermittent neutropenia. Patients and methods The aim of the study was to determine which of the above clinical features were the best indicators for the presence of VPS13B gene mutations in a series of 34 patients with suspected Cohen syndrome referred for molecular analysis of VPS13B. Results 14 VPS13B gene mutations were identified in 12 patients, and no mutation was found in 22 patients. The presence of chorioretinal dystrophy (92% vs 32%, p=0.0023), intermittent neutropenia (92% vs 5%, p<0.001), and postnatal microcephaly (100% vs 48%, p=0.0045) was significantly higher in the group of patients with a VPS13B gene mutation compared to the group of patients without a mutation. All patients with VPS13B mutations had chorioretinal dystrophy and/or intermittent neutropenia. The Kolehmainen diagnostic criteria provided 100% sensibility and 77% specificity when applied to this series. Conclusion From this study and a review of more than 160 genotyped cases from the literature, it is concluded that, given the large size of the gene, VPS13B screening is not indicated in the absence of chorioretinal dystrophy or neutropenia in patients aged over 5 years. The follow-up of young patients could be a satisfactory alternative unless there are some reproductive issues. [ABSTRACT FROM AUTHOR]

Objectives To develop a comprehensive mutation analysis system with a high rate of detection, to develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and to look for genotype—phenotype correlations in the X-linked recessive disorder, L1 syndrome. Methods DNA from 367 referred patients was analysed for mutations in the coding sequences of the gene. A subgroup of 100 patients was also investigated for mutations in regulatory sequences and for large duplications. Clinical data for 106 patients were collected and used for statistical analysis. Results 68 different mutations were detected in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, the mutation detection rate was 66% compared with 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (OR 10.4, 95% CI 3.6 to 30.1). The type of mutation affects the severity of L1 syndrome. Children with a truncating mutation were more likely to die before the age of 3 than those with a missense mutation (52% vs 8%; p=0.02). Conclusions We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients' clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven. [ABSTRACT FROM AUTHOR]