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Modern applications of neurogenetics
Chapter 13
Modern applications of neurogenetics Dolores Gonzalez Moron and Marcelo A. Kauffman Neurogenetics Clinic, Hospital JM Ramos Mejia, Buenos Aires, Argentina
We have seen an exponential growth in the knowledge of the genetic basis of diseases during the past 50 years [1]. In about a third of monogenetic disorders the nervous system is compromised. Every tertiary hospital should consider incorporating neurogenetic clinics, in which multidisciplinary teams could offer a thorough assistance for patients affected by neurogenetic conditions [2].
The practice of neurogenetics DNA sequencing technologies are advancing and therapeutics for some conditions are emerging [3]. A large number of conditions can be tested for, at reduced cost and with improved diagnostic accuracy [4]. Single genes, panels of genes, whole exomes, or even whole genomes can be addressed whenever necessary [5,6].
Indications A positive family history or the onset of disorders at early age is important; however, they are not the only clues for neurogenetic conditions [7]. Almost 50% of neurogenetic conditions starting in infancy are caused by so called de novo mutations, presenting as sporadic cases [8]. On the other hand, not less than a third of neurogenetic disorders start at adult age [9]. Neurogenetic disorders should always be considered, especially when the observed phenotype is complex, or belongs to the so-called “neurogenetic niches,” such as cerebral palsy, malformations of cortical development, intellectual disability, epilepsy, ataxia, movement disorders, early onset dementia, and neuromuscular disorders.
The neurogenetic niches Cerebral palsy is an umbrella term usually applied for any patient exhibiting a congenital neurological deficit, with a very slow progressive course or not progressive at all. An acquired or traumatic etiology is frequently assumed, even
in cases lacking clear history. De novo point mutations in KCNC3, ITPR1, and SPTBN2 genes were unearthed using next-generation sequencing assays, in a large cohort of individuals with ataxic cerebral palsy [10]. Exome sequencing also identified de novo mutations in different genes such as TUBA1A, SCN8A, and KDM5C [11]. In a cohort of patients suffering from hemiplegic cerebral palsy, Zarrei et al. detected de novo CNVs and/or sex chromosome abnormalities in 7.2% of probands, impacting important developmental genes such as GRIK2, LAMA1, DMD, PTPRM, and DIP2C [12].
Intellectual deficit Historically, a specific diagnosis has been achieved in only a small minority of children suffering from intellectual disability; however, results are improving [13]. In almost half of the patients [14], an etiology can be found. The vast majority are de novo truncating mutations in any of the hundreds of genes recently implied in intellectual disabilities. Each of these genes accounts for less than 1% of cases, highlighting the extreme genetic heterogeneity of this population [15]. Health economic studies suggest that testing is most cost-effective when performed early in the patient’s diagnostic odyssey [16]. Nevertheless, identifying the cause of these disorders is of paramount importance for genetic counseling and therapy, whenever it is available.
Epilepsy Several genes are causes of monogenic epilepsies, and hundreds are risk factors for complex genetic epilepsies. Genetic testing plays a pivotal role [17]. In certain conditions, the likelihood of finding a genetic etiology may be higher, particularly in epileptic encephalopathies, in which analogously to intellectual disability, the main findings are de novo truncating mutations within extreme genetic heterogeneity architecture [18]. Furthermore, accurate genetic diagnosis may define specific treatments, such as in case of
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Dravet Syndrome [19] and KCNT1-related epilepsy [20], among others. The diagnostic yield in this field has been quite variable, ranging from about 10% in older reports to about 50% in recent ones [21]. In children with newly diagnosed epilepsy, an overall yield of 40.4% was accomplished with various genetic tests [22]. Exome sequencing and multigene panel testing are the most cost-effective procedures for epilepsy [23].
Movement disorders Molecular genetics has allowed better classifications and definitions of different clinical syndromes [24], with translation into clinical practice [25]. Accurate genetic diagnoses in movement disorders often pave the way for specific and disease modifying treatments [26]. However, experienced professionals need to characterize the complex phenotypes shown by such patients, in order to improve diagnosis and clinical care [27].
Dementia About 20% of the population aged 55 years and older has a family history of dementia [28]. For most, this is due to a genetically complex disease, where many variations of small effects interact to increase risk of dementia [29]. Early onset dementias are classified as rare diseases (less than 1%) [30]. Good assessment of the cognitive phenotype is of paramount importance, for obtaining better diagnostic yields and rational use of genetic tests. Phenotype-guided ordering of single gene, or small multigene panels, can result in high diagnostic yields [31]. Early onset Alzheimer disease is often caused by mutations in APP, PSEN1, and PSEN2 [32]. Frontotemporal dementia might be caused by an abnormal number of repeats of a pentanucleotide in C9orf72 [33] or point mutations in PGRN, MAPT, VCP, among other genes less frequently compromised [34]. In addition, more than 30 monogenic disorders present with or include dementia as a clinical symptom [35]. More comprehensive approaches are recommended, after excluding the more prevalent phenotypes [36].
Neuromuscular abnormalities Hundreds of individual disorders can affect muscle, nerve, motor neuron, or neuromuscular junction. Their onset is any time, from in utero until old age. They are most often genetic, thus markedly benefiting from sequencing technologies [37]. Any type of mutation in human DNA can cause genetic neuromuscular disorders. Exome and multigene panel sequencing are recommended early in the evaluation of neuromuscular disorders, in many cases clarifying diagnosis and minimizing invasive investigation [38]. Diagnostic yields of 26%e65% emphasize the importance of shortening the diagnostic odyssey, minimizing unnecessary testing, and providing opportunities for
clinical and investigational therapies in these heterogeneous group of patients [39,40].
Genetic counseling Diagnosis should be as specific as possible [41]. It is not finalized until the causing molecular defect is individualized. Recurrence risk assessment also becomes an important part of genetic counseling [42]. Inheritance pattern associated with the genetic defect, penetrance, and age of onset, as well as de novo mutations inferred from the site and time of development of the anomaly, are all relevant. Prognosis, natural history, and referral to disease-specific support groups should not be neglected [43].
Neurogenetics on a personalized research-based clinic We have implemented a clinic and a laboratory specialized in neurogenetics, which make use of their own resources, within a framework of research [2]. We demonstrated the clinical utility of exome sequencing in our patient cohort, obtaining a diagnostic yield of 40% among a diverse group of neurological disorders [44]. Furthermore, we were able to expand the phenotypic spectrum of known genes, and identify new pathogenic variants in several genes [45]. Preliminary cost-analysis lends support to the assertion that exome sequencing is more cost-effective than other molecular diagnostic approaches based on single- or panelgene analysis. Our results were comparable with previous experiences reported by others [5], and highlight the advantages of working as a personalized research group, where phenotypic and genotypic information can be thoughtfully assessed, in contrast to commercial diagnostic laboratories that only have access to focused, heterogeneous, and often less informative clinical phenotypic reports, filled by the external ordering physician. This interdisciplinary work proved useful for reducing the long diagnostic delays, impacting medical management, and optimizing genetic counseling for these families. We have specially addressed molecular diagnosis of ataxias [46,47] and malformations of cortical development [48]. Ataxias have a worldwide prevalence of about 3e5 cases per 100,000 [49]. More than 100 conditions can be classified as ataxic disorder. Pursuing diagnosis can require the use of different molecular genetic techniques. A great number of dominant ataxias and the most frequent recessive ataxia, Friedreich’s ataxia, are caused by abnormally repetitive sequences of trinucleotides [50]. Thus, molecular diagnosis requires assays able to quantify the number of these repeats. On the other hand, the rest of dominant and recessive ataxias are caused by point mutations or short indels. Its diagnosis is amenable to sequencing based-assays, such as multigene panel sequencing or exome sequencing. Applying both types of assays, we were able to identify the causing molecular defect in about a third of our cohort. The
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most common ataxias in our population were SCA type 2, SCA type 3 and Friedreich’s ataxia. Exome sequencing led us to identify the genetic cause, in about a half of those cases negative for abnormal repeat trinucleotides. This figure is comparable to others [51]. The malformations of cortical development constitute another neurogenetic niche that specially captivated our attention in the past years. Human brain cortex development is a complex and highly regulated process that involves neural proliferation, differentiation, migration, and postmigrational development [52] (Table 13.1). Disruption in any of these steps can result in structural brain anomalies called Malformations of Cortical Development (MCDs), which are an important cause of epilepsy and neurodevelopment delay [53]. There are more than 30 types of MCDs classified in three major groups depending on the primary developmental step interrupted [54,55]. Although a few MCDs can be caused by environmental or acquired factors (e.g., CMV infection), most probably, the majority of the MCDs have a genetic origin. Historically linkage analysis, positional cloning, and gene sequencing have allowed to identify some genetic causes of MCDs; however, the genetic background of a very high proportion of MCDs remained elusive. The advent of high-throughput
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next-generation sequencing changed immensely our knowledge of the molecular basis of MCDs. The new technologies allowed to identify new candidate genes, to expand the phenotypic spectra of known genes, and to achieve a better understanding of the molecular pathways in brain development and pathologic processes underlying MCDs [56,57]. This notion can be illustrated with many types of MCDs, for example, the Lissencephaly (LIS) spectrum. LIS comprises a spectrum of malformations caused by a defect in neuronal migration that includes agyria, pachygyria, and subcortical band heterotopia (SBH) [58,59]. Of the 20 genes associated to LIS more than a half has been discovered in the past 6 years [60]. A targeted sequencing panel of 17 LIS-associated genes was applied by Di Donato et al. [60], recently, to identify a causal mutation in 34% of 216 children with unexplained LIS. These results added to historical molecular analysis (deletion 17p13.3 and DCX, LIS1, ARX sequencing) detected mutations in 81% of a cohort of 811 LIS patients and supplied relevant data regarding LIS-associated genes prevalence, phenotypic expression, and allowed a new biological network-based classification of LIS.
TABLE 13.1 Genetic etiologies of MCDS. Associated pathways and etiology
MCT type
Group
Causing genes
Microcephaly
Group I
MCPH1, CENPJ, CDK5RAP2, WDR62, NDE1, NDE1, ASPM, CDK5RAP2, TUBA1A, TUBB2B, TUBB3, TUBG1, LIS1, DCX, DYNC1H, KIF5C, and NDE1
Neurogenesis and cell replication, tubulin, and microtubule-associated proteins (MAP)
Megalencephaly spectrum
Group I
WDR62, PIK3R2, PIK3CA, and AKT3
mTOR
FCD type IIA
Group I
MTOR, DEPDC5, PIK3CA
mTOR
FCD type IIB
Group I
MTOR, DEPDC5, NPRL3
mTOR
Tubulinopathies (lissencephaly, basal ganglia dysgenesia, cortical dysgryria)
Group II
TUBA1A, TUBB2B, TUBB3, TUBB, TUBA (,TUBG1, LIS1, DCX, DYNC1H, KIF5C, KIF2A, NDE1
Microtubule structure and function, tubulins, and centrosome expressed MAPs
Lissencephalies
Group II
ARX, RELN, VLDR, ACTB, ACTG1, CDK5
Reelin, forebrain transcriptional regulation
Gray matter heterotopia
Group II
FLNA, ARGEF2, ERMARD, FAT4, DCHS1, LRP2, C6orf70, NEDD4L
Actin filaments/Neuroepithelium/ mTOR
Cobblestone malformations
Group II
GPR56, LAMB1; LAMB2, LAMC3, SRD5A3
Dystroglycanopathies
Polymicrogyria (PMG)
Group III
GPR56, TUBB2B, SRPX2, TBR2, PAX6, NDE1, WDR62, FH, OCLN, CHD7, RAB3GAP1, RAB18, NEDD4L, MTOR, PIK3R2
mTOR, microtubule structure and function
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In our center, to contribute to phenotypic expansion and to collaborate to elucidate the pathological pathways in MCDs, we searched for germinal and somatic mutations in a cohort of 38 patients with neuronal migration disorders (Periventricular nodular heterotopia, Subcortical band heterotopia, and Lissencephaly). A conclusive genetic diagnosis was achieved in 14 patients. Remarkably, we found a somatic mutation in four out of twelve patients in whom we applied a targeted high-coverage
NGS (mean coverage of about 4000). This technique allowed us to detect mosaic mutations with a very low alternate allele frequency (between 10% and 15%) from peripheral blood samples [48]. Thus, it provides a unique opportunity for the study of brain mosaic diseases overcoming two of its historical difficulties: the limited accessibility to brain tissue and Sanger low sensibility to detect mosaic variants (threshold of 15%e20%) [61] (Fig. 13.1). Other MCDs that have largely benefited from new sequencing
FIGURE 13.1 Familiar, radiological and molecular findings in four individuals of our MCD cohort (MDC1019, MDC1020, MDC1070, and MDC1034). A-Case MDC1019 and MDC1020 illustrate the expanded phenotype of FLNA mutations which ranged in this pair of siblings from diffuse bilateral heterotopic periventricular nodules responsible for refractory epilepsy (MDC 1019) to an isolated nodule in an apparently asymptomatic patient (MDC 1020). A1 Pedigree A2. Coronal T1 MRI from MDC 1020 participant. The image shows an isolated heterotopic nodule adjacent to the right lateral ventricle (arrow). A3. Sanger sequencing of FLNA gene showing the NM_001110556.1: c.4159G>A mutation. B-Case MDC1070 represents the Lissencephaly spectrum. In this case a mosaic PAFAH1B1 mutation resulted in a less severe phenotype of SBH with posterior predominance. B1 Pedigree B2. MDC 1070 MRI. Inversion-Recovery Coronal MRI images show a posterior (P > A) band of subcortical heterotopia as well as simplified gyri and a thin layer of white matter between the cortex and band. B3. NGS (left) and Sanger sequencing after subcloning (right) of PAFAH1B1 gene showing the presence of the somatic mutation NM_000430: c.628G>C; p.A210P (alternate allele read frequency 14.99%). C-Case MDC1034 illustrates a somatic mutation of DCX. Similarly to case MDC 1070, this mosaic mutation, although present in an X-linked gene in a male patient, caused a less severe phenotype (HBS). C1 Pedigree C2. Coronal T1-WI shows a diffuse, thick (>12 mm) subcortical heterotopic band. C3. NGS (left) and Sanger (right) sequencing for DCX gene showing the NM_178152.1: c.176G>A mutation. Please consider that the Sanger sequencing was performed on the coding strand (reverse of reference).
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technologies are the megalencephaly, dysplasic megalencephaly, hemimegalencephaly, and focal cortical dysplasias. Until recently, these malformations were not well understood in pathogenic terms, specially the FCD. However, the focal nature of these lesions and the pathological resemblance to tubers in tuberous sclerosis led to the idea that somatic mosaic mutation in the mTOR pathway (that includes tuberous sclerosis associated genes: TSC1 and TSC2) could be the responsible. This hypothesis was in part confirmed by the identification of mosaic mutations in many mTOR genes (DEPDC5, AKT3, TSC1, PIK3CA, PIK3R2, mTOR, etc.) in hemimegalencephaly, megalencephaly, and FCD type 2 [62e64]. In our cohort of patients with MCDs, we identified a somatic mutation in the RHEB gene through high depth and ultrahigh depth next generation sequencing in a patient with hemimegalencephaly and drug resistant epilepsy. It was only present in the brain tissue at a mutant allele fraction of 21%, being undetectable by Sanger. The RHEB gene encodes a protein that has a key role in growth and cell cycle progression due to its action in regulation of the mTOR pathway. Hyperactivation of the mTORC1 was observed in dysmorphic neurons of our patient, in contrast to apparently normal adjacent neurons [65]. The acknowledgment of the mTOR pathway in the generation of cortical malformations has implications not only in a pathological, molecular, and diagnosis sphere but also provides a therapeutic window due to Rapamicyn’s ability to inhibit this pathway [66]. The practice of neurogenetics is a work of multidisciplinary teams. The members of these teams should be proficient in the five main components that constitute a thorough evaluation and management of patient with neurogenetic diseases (modified from 7): (a) an adequate knowledge of the neurology of these disorders; (b) sufficient experience and training in the genetic of these disorders; (c) interpersonal skills required for genetic counseling; (d) have a family perspective in order to recognize those family members at risk that will necessitate of these teams’ work as well and (e) comprehensive knowledge of state-of-the-art diagnostic technologies applicable in this field. It is our belief, that following these premises, we will continue to solve and shorten the many diagnostic odysseys historically suffered by these complex patients.
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[61] Qin L, Wang J, Tian X, Yu H, Truong C, Mitchell JJ, et al. Detection and quantification of mosaic mutations in disease genes by nextgeneration sequencing. J. Mol. Diagn 2016;18(3):446e53. [62] Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, et al. De novo somatic mutations in components of the PI3K-AKT3mTOR pathway cause hemimegalencephaly. Nat. Genet. 2012;44(8):941e5. [63] Leventer RJ, Scerri T, Marsh AP, Pope K, Gillies G, Maixner W, et al. Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR. Neurology 2015;84(20):2029e32. [64] Lim JS, Kim WI, Kang HC, Kim SH, Park AH, Park EK, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat. Med. 2015;21(4):395e400. [65] Salinas V, Vega P, Piccirilli MV, Chicco C, Ciraolo C, Christiansen S, et al. Identification of a somatic mutation in the RHEB gene through high depth and ultra-high depth next generation sequencing in a patient with Hemimegalencephaly and drug resistant Epilepsy. Eur. J. Med. Genet. 2018 in press. [66] Way SW, Rozas NS, Wu HC, McKenna 3rd J, Reith RM, Hashmi SS, et al. The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. Hum. Mol. Genet. 2012;21(14):3226e36.
Modern applications of neurogenetics Dolores Gonzalez Moron and Marcelo A. Kauffman Neurogenetics Clinic, Hospital JM Ramos Mejia, Buenos Aires, Argentina
We have seen an exponential growth in the knowledge of the genetic basis of diseases during the past 50 years [1]. In about a third of monogenetic disorders the nervous system is compromised. Every tertiary hospital should consider incorporating neurogenetic clinics, in which multidisciplinary teams could offer a thorough assistance for patients affected by neurogenetic conditions [2].
The practice of neurogenetics DNA sequencing technologies are advancing and therapeutics for some conditions are emerging [3]. A large number of conditions can be tested for, at reduced cost and with improved diagnostic accuracy [4]. Single genes, panels of genes, whole exomes, or even whole genomes can be addressed whenever necessary [5,6].
Indications A positive family history or the onset of disorders at early age is important; however, they are not the only clues for neurogenetic conditions [7]. Almost 50% of neurogenetic conditions starting in infancy are caused by so called de novo mutations, presenting as sporadic cases [8]. On the other hand, not less than a third of neurogenetic disorders start at adult age [9]. Neurogenetic disorders should always be considered, especially when the observed phenotype is complex, or belongs to the so-called “neurogenetic niches,” such as cerebral palsy, malformations of cortical development, intellectual disability, epilepsy, ataxia, movement disorders, early onset dementia, and neuromuscular disorders.
The neurogenetic niches Cerebral palsy is an umbrella term usually applied for any patient exhibiting a congenital neurological deficit, with a very slow progressive course or not progressive at all. An acquired or traumatic etiology is frequently assumed, even
in cases lacking clear history. De novo point mutations in KCNC3, ITPR1, and SPTBN2 genes were unearthed using next-generation sequencing assays, in a large cohort of individuals with ataxic cerebral palsy [10]. Exome sequencing also identified de novo mutations in different genes such as TUBA1A, SCN8A, and KDM5C [11]. In a cohort of patients suffering from hemiplegic cerebral palsy, Zarrei et al. detected de novo CNVs and/or sex chromosome abnormalities in 7.2% of probands, impacting important developmental genes such as GRIK2, LAMA1, DMD, PTPRM, and DIP2C [12].
Intellectual deficit Historically, a specific diagnosis has been achieved in only a small minority of children suffering from intellectual disability; however, results are improving [13]. In almost half of the patients [14], an etiology can be found. The vast majority are de novo truncating mutations in any of the hundreds of genes recently implied in intellectual disabilities. Each of these genes accounts for less than 1% of cases, highlighting the extreme genetic heterogeneity of this population [15]. Health economic studies suggest that testing is most cost-effective when performed early in the patient’s diagnostic odyssey [16]. Nevertheless, identifying the cause of these disorders is of paramount importance for genetic counseling and therapy, whenever it is available.
Epilepsy Several genes are causes of monogenic epilepsies, and hundreds are risk factors for complex genetic epilepsies. Genetic testing plays a pivotal role [17]. In certain conditions, the likelihood of finding a genetic etiology may be higher, particularly in epileptic encephalopathies, in which analogously to intellectual disability, the main findings are de novo truncating mutations within extreme genetic heterogeneity architecture [18]. Furthermore, accurate genetic diagnosis may define specific treatments, such as in case of
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Dravet Syndrome [19] and KCNT1-related epilepsy [20], among others. The diagnostic yield in this field has been quite variable, ranging from about 10% in older reports to about 50% in recent ones [21]. In children with newly diagnosed epilepsy, an overall yield of 40.4% was accomplished with various genetic tests [22]. Exome sequencing and multigene panel testing are the most cost-effective procedures for epilepsy [23].
Movement disorders Molecular genetics has allowed better classifications and definitions of different clinical syndromes [24], with translation into clinical practice [25]. Accurate genetic diagnoses in movement disorders often pave the way for specific and disease modifying treatments [26]. However, experienced professionals need to characterize the complex phenotypes shown by such patients, in order to improve diagnosis and clinical care [27].
Dementia About 20% of the population aged 55 years and older has a family history of dementia [28]. For most, this is due to a genetically complex disease, where many variations of small effects interact to increase risk of dementia [29]. Early onset dementias are classified as rare diseases (less than 1%) [30]. Good assessment of the cognitive phenotype is of paramount importance, for obtaining better diagnostic yields and rational use of genetic tests. Phenotype-guided ordering of single gene, or small multigene panels, can result in high diagnostic yields [31]. Early onset Alzheimer disease is often caused by mutations in APP, PSEN1, and PSEN2 [32]. Frontotemporal dementia might be caused by an abnormal number of repeats of a pentanucleotide in C9orf72 [33] or point mutations in PGRN, MAPT, VCP, among other genes less frequently compromised [34]. In addition, more than 30 monogenic disorders present with or include dementia as a clinical symptom [35]. More comprehensive approaches are recommended, after excluding the more prevalent phenotypes [36].
Neuromuscular abnormalities Hundreds of individual disorders can affect muscle, nerve, motor neuron, or neuromuscular junction. Their onset is any time, from in utero until old age. They are most often genetic, thus markedly benefiting from sequencing technologies [37]. Any type of mutation in human DNA can cause genetic neuromuscular disorders. Exome and multigene panel sequencing are recommended early in the evaluation of neuromuscular disorders, in many cases clarifying diagnosis and minimizing invasive investigation [38]. Diagnostic yields of 26%e65% emphasize the importance of shortening the diagnostic odyssey, minimizing unnecessary testing, and providing opportunities for
clinical and investigational therapies in these heterogeneous group of patients [39,40].
Genetic counseling Diagnosis should be as specific as possible [41]. It is not finalized until the causing molecular defect is individualized. Recurrence risk assessment also becomes an important part of genetic counseling [42]. Inheritance pattern associated with the genetic defect, penetrance, and age of onset, as well as de novo mutations inferred from the site and time of development of the anomaly, are all relevant. Prognosis, natural history, and referral to disease-specific support groups should not be neglected [43].
Neurogenetics on a personalized research-based clinic We have implemented a clinic and a laboratory specialized in neurogenetics, which make use of their own resources, within a framework of research [2]. We demonstrated the clinical utility of exome sequencing in our patient cohort, obtaining a diagnostic yield of 40% among a diverse group of neurological disorders [44]. Furthermore, we were able to expand the phenotypic spectrum of known genes, and identify new pathogenic variants in several genes [45]. Preliminary cost-analysis lends support to the assertion that exome sequencing is more cost-effective than other molecular diagnostic approaches based on single- or panelgene analysis. Our results were comparable with previous experiences reported by others [5], and highlight the advantages of working as a personalized research group, where phenotypic and genotypic information can be thoughtfully assessed, in contrast to commercial diagnostic laboratories that only have access to focused, heterogeneous, and often less informative clinical phenotypic reports, filled by the external ordering physician. This interdisciplinary work proved useful for reducing the long diagnostic delays, impacting medical management, and optimizing genetic counseling for these families. We have specially addressed molecular diagnosis of ataxias [46,47] and malformations of cortical development [48]. Ataxias have a worldwide prevalence of about 3e5 cases per 100,000 [49]. More than 100 conditions can be classified as ataxic disorder. Pursuing diagnosis can require the use of different molecular genetic techniques. A great number of dominant ataxias and the most frequent recessive ataxia, Friedreich’s ataxia, are caused by abnormally repetitive sequences of trinucleotides [50]. Thus, molecular diagnosis requires assays able to quantify the number of these repeats. On the other hand, the rest of dominant and recessive ataxias are caused by point mutations or short indels. Its diagnosis is amenable to sequencing based-assays, such as multigene panel sequencing or exome sequencing. Applying both types of assays, we were able to identify the causing molecular defect in about a third of our cohort. The
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most common ataxias in our population were SCA type 2, SCA type 3 and Friedreich’s ataxia. Exome sequencing led us to identify the genetic cause, in about a half of those cases negative for abnormal repeat trinucleotides. This figure is comparable to others [51]. The malformations of cortical development constitute another neurogenetic niche that specially captivated our attention in the past years. Human brain cortex development is a complex and highly regulated process that involves neural proliferation, differentiation, migration, and postmigrational development [52] (Table 13.1). Disruption in any of these steps can result in structural brain anomalies called Malformations of Cortical Development (MCDs), which are an important cause of epilepsy and neurodevelopment delay [53]. There are more than 30 types of MCDs classified in three major groups depending on the primary developmental step interrupted [54,55]. Although a few MCDs can be caused by environmental or acquired factors (e.g., CMV infection), most probably, the majority of the MCDs have a genetic origin. Historically linkage analysis, positional cloning, and gene sequencing have allowed to identify some genetic causes of MCDs; however, the genetic background of a very high proportion of MCDs remained elusive. The advent of high-throughput
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next-generation sequencing changed immensely our knowledge of the molecular basis of MCDs. The new technologies allowed to identify new candidate genes, to expand the phenotypic spectra of known genes, and to achieve a better understanding of the molecular pathways in brain development and pathologic processes underlying MCDs [56,57]. This notion can be illustrated with many types of MCDs, for example, the Lissencephaly (LIS) spectrum. LIS comprises a spectrum of malformations caused by a defect in neuronal migration that includes agyria, pachygyria, and subcortical band heterotopia (SBH) [58,59]. Of the 20 genes associated to LIS more than a half has been discovered in the past 6 years [60]. A targeted sequencing panel of 17 LIS-associated genes was applied by Di Donato et al. [60], recently, to identify a causal mutation in 34% of 216 children with unexplained LIS. These results added to historical molecular analysis (deletion 17p13.3 and DCX, LIS1, ARX sequencing) detected mutations in 81% of a cohort of 811 LIS patients and supplied relevant data regarding LIS-associated genes prevalence, phenotypic expression, and allowed a new biological network-based classification of LIS.
TABLE 13.1 Genetic etiologies of MCDS. Associated pathways and etiology
MCT type
Group
Causing genes
Microcephaly
Group I
MCPH1, CENPJ, CDK5RAP2, WDR62, NDE1, NDE1, ASPM, CDK5RAP2, TUBA1A, TUBB2B, TUBB3, TUBG1, LIS1, DCX, DYNC1H, KIF5C, and NDE1
Neurogenesis and cell replication, tubulin, and microtubule-associated proteins (MAP)
Megalencephaly spectrum
Group I
WDR62, PIK3R2, PIK3CA, and AKT3
mTOR
FCD type IIA
Group I
MTOR, DEPDC5, PIK3CA
mTOR
FCD type IIB
Group I
MTOR, DEPDC5, NPRL3
mTOR
Tubulinopathies (lissencephaly, basal ganglia dysgenesia, cortical dysgryria)
Group II
TUBA1A, TUBB2B, TUBB3, TUBB, TUBA (,TUBG1, LIS1, DCX, DYNC1H, KIF5C, KIF2A, NDE1
Microtubule structure and function, tubulins, and centrosome expressed MAPs
Lissencephalies
Group II
ARX, RELN, VLDR, ACTB, ACTG1, CDK5
Reelin, forebrain transcriptional regulation
Gray matter heterotopia
Group II
FLNA, ARGEF2, ERMARD, FAT4, DCHS1, LRP2, C6orf70, NEDD4L
Actin filaments/Neuroepithelium/ mTOR
Cobblestone malformations
Group II
GPR56, LAMB1; LAMB2, LAMC3, SRD5A3
Dystroglycanopathies
Polymicrogyria (PMG)
Group III
GPR56, TUBB2B, SRPX2, TBR2, PAX6, NDE1, WDR62, FH, OCLN, CHD7, RAB3GAP1, RAB18, NEDD4L, MTOR, PIK3R2
mTOR, microtubule structure and function
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In our center, to contribute to phenotypic expansion and to collaborate to elucidate the pathological pathways in MCDs, we searched for germinal and somatic mutations in a cohort of 38 patients with neuronal migration disorders (Periventricular nodular heterotopia, Subcortical band heterotopia, and Lissencephaly). A conclusive genetic diagnosis was achieved in 14 patients. Remarkably, we found a somatic mutation in four out of twelve patients in whom we applied a targeted high-coverage
NGS (mean coverage of about 4000). This technique allowed us to detect mosaic mutations with a very low alternate allele frequency (between 10% and 15%) from peripheral blood samples [48]. Thus, it provides a unique opportunity for the study of brain mosaic diseases overcoming two of its historical difficulties: the limited accessibility to brain tissue and Sanger low sensibility to detect mosaic variants (threshold of 15%e20%) [61] (Fig. 13.1). Other MCDs that have largely benefited from new sequencing
FIGURE 13.1 Familiar, radiological and molecular findings in four individuals of our MCD cohort (MDC1019, MDC1020, MDC1070, and MDC1034). A-Case MDC1019 and MDC1020 illustrate the expanded phenotype of FLNA mutations which ranged in this pair of siblings from diffuse bilateral heterotopic periventricular nodules responsible for refractory epilepsy (MDC 1019) to an isolated nodule in an apparently asymptomatic patient (MDC 1020). A1 Pedigree A2. Coronal T1 MRI from MDC 1020 participant. The image shows an isolated heterotopic nodule adjacent to the right lateral ventricle (arrow). A3. Sanger sequencing of FLNA gene showing the NM_001110556.1: c.4159G>A mutation. B-Case MDC1070 represents the Lissencephaly spectrum. In this case a mosaic PAFAH1B1 mutation resulted in a less severe phenotype of SBH with posterior predominance. B1 Pedigree B2. MDC 1070 MRI. Inversion-Recovery Coronal MRI images show a posterior (P > A) band of subcortical heterotopia as well as simplified gyri and a thin layer of white matter between the cortex and band. B3. NGS (left) and Sanger sequencing after subcloning (right) of PAFAH1B1 gene showing the presence of the somatic mutation NM_000430: c.628G>C; p.A210P (alternate allele read frequency 14.99%). C-Case MDC1034 illustrates a somatic mutation of DCX. Similarly to case MDC 1070, this mosaic mutation, although present in an X-linked gene in a male patient, caused a less severe phenotype (HBS). C1 Pedigree C2. Coronal T1-WI shows a diffuse, thick (>12 mm) subcortical heterotopic band. C3. NGS (left) and Sanger (right) sequencing for DCX gene showing the NM_178152.1: c.176G>A mutation. Please consider that the Sanger sequencing was performed on the coding strand (reverse of reference).
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technologies are the megalencephaly, dysplasic megalencephaly, hemimegalencephaly, and focal cortical dysplasias. Until recently, these malformations were not well understood in pathogenic terms, specially the FCD. However, the focal nature of these lesions and the pathological resemblance to tubers in tuberous sclerosis led to the idea that somatic mosaic mutation in the mTOR pathway (that includes tuberous sclerosis associated genes: TSC1 and TSC2) could be the responsible. This hypothesis was in part confirmed by the identification of mosaic mutations in many mTOR genes (DEPDC5, AKT3, TSC1, PIK3CA, PIK3R2, mTOR, etc.) in hemimegalencephaly, megalencephaly, and FCD type 2 [62e64]. In our cohort of patients with MCDs, we identified a somatic mutation in the RHEB gene through high depth and ultrahigh depth next generation sequencing in a patient with hemimegalencephaly and drug resistant epilepsy. It was only present in the brain tissue at a mutant allele fraction of 21%, being undetectable by Sanger. The RHEB gene encodes a protein that has a key role in growth and cell cycle progression due to its action in regulation of the mTOR pathway. Hyperactivation of the mTORC1 was observed in dysmorphic neurons of our patient, in contrast to apparently normal adjacent neurons [65]. The acknowledgment of the mTOR pathway in the generation of cortical malformations has implications not only in a pathological, molecular, and diagnosis sphere but also provides a therapeutic window due to Rapamicyn’s ability to inhibit this pathway [66]. The practice of neurogenetics is a work of multidisciplinary teams. The members of these teams should be proficient in the five main components that constitute a thorough evaluation and management of patient with neurogenetic diseases (modified from 7): (a) an adequate knowledge of the neurology of these disorders; (b) sufficient experience and training in the genetic of these disorders; (c) interpersonal skills required for genetic counseling; (d) have a family perspective in order to recognize those family members at risk that will necessitate of these teams’ work as well and (e) comprehensive knowledge of state-of-the-art diagnostic technologies applicable in this field. It is our belief, that following these premises, we will continue to solve and shorten the many diagnostic odysseys historically suffered by these complex patients.
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