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OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). INTERPRETATION: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.
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Edad de Inicio , Discapacidades del Desarrollo , Leucodistrofia Metacromática , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/patología , Leucodistrofia Metacromática/genética , Discapacidades del Desarrollo/diagnóstico , Masculino , Femenino , Preescolar , Lactante , Niño , Adolescente , Estudios de Cohortes , Progresión de la EnfermedadRESUMEN
We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva samples. Our cohort comprised 370 individuals who had testing of both, 224 with syndromic intellectual disability (ID) and 146 with isolated ID. Mosaic pathogenic CNVs or aneuploidy were detected in saliva but not in blood in 20/370 (4.4%). All 20 individuals had syndromic ID, accounting for 9.1% of the syndromic ID sub-cohort. Pathogenic CNVs were large in size (median of 46 Mb), and terminal in nature, with median mosaicism of 27.5% (not exceeding 40%). By contrast, non-mosaic pathogenic CNVs were 100% concordant between blood and saliva, considerably smaller in size (median of 0.65 Mb), and predominantly interstitial in location. Given that salivary microarray testing has increased diagnostic utility over blood in individuals with syndromic ID, we recommend it as a first-tier testing in this group.
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Discapacidad Intelectual , Niño , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Saliva , Discapacidades del Desarrollo/genética , Aberraciones Cromosómicas , Mosaicismo , Genómica , Variaciones en el Número de Copia de ADNRESUMEN
Globally, there is a recognised need that all populations should be able to access the benefits of genomics and precision medicine. However, achieving this remains constrained by a paucity of data that quantifies access to clinical genomics, particularly amongst Indigenous populations. Using administrative data from clinical genetic health services across three Australian jurisdictions (states/territories), we investigate disparities in the scheduling and attendance of appointments among Aboriginal and/or Torres Strait Islander people, compared to non-Indigenous people. For 14,870 appointments scheduled between 2014-2018, adjusted Multivariate Poisson Regression models revealed that Aboriginal and/or Torres Strait Islander people were scheduled fewer appointments (IRR 0.73 [0.68-0.80], <0.001) and attended at lower rates (IRR 0.85 [0.78-0.93], <0.001). Within this population, adults, females, remote residents, and those presenting in relation to cancer or prenatal indications experienced the greatest disparity in access. These results provide important baseline data related to disparities in access to clinical genomics in Australia.
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Pueblos Indígenas , Nativos de Hawái y Otras Islas del Pacífico , Adulto , Australia/epidemiología , Femenino , Servicios de Salud , Humanos , Nativos de Hawái y Otras Islas del Pacífico/genética , Embarazo , Grupos RacialesRESUMEN
BACKGROUND: Clinical exome sequencing typically achieves diagnostic yields of 30%-57.5% in individuals with monogenic rare diseases. Undiagnosed diseases programmes implement strategies to improve diagnostic outcomes for these individuals. AIM: We share the lessons learnt from the first 3 years of the Undiagnosed Diseases Program-Victoria, an Australian programme embedded within a clinical genetics service in the state of Victoria with a focus on paediatric rare diseases. METHODS: We enrolled families who remained without a diagnosis after clinical genomic (panel, exome or genome) sequencing between 2016 and 2018. We used family-based exome sequencing (family ES), family-based genome sequencing (family GS), RNA sequencing (RNA-seq) and high-resolution chromosomal microarray (CMA) with research-based analysis. RESULTS: In 150 families, we achieved a diagnosis or strong candidate in 64 (42.7%) (37 in known genes with a consistent phenotype, 3 in known genes with a novel phenotype and 24 in novel disease genes). Fifty-four diagnoses or strong candidates were made by family ES, six by family GS with RNA-seq, two by high-resolution CMA and two by data reanalysis. CONCLUSION: We share our lessons learnt from the programme. Flexible implementation of multiple strategies allowed for scalability and response to the availability of new technologies. Broad implementation of family ES with research-based analysis showed promising yields post a negative clinical singleton ES. RNA-seq offered multiple benefits in family ES-negative populations. International data sharing strategies were critical in facilitating collaborations to establish novel disease-gene associations. Finally, the integrated approach of a multiskilled, multidisciplinary team was fundamental to having diverse perspectives and strategic decision-making.
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Enfermedades no Diagnosticadas , Australia , Exoma , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/epidemiología , Enfermedades Raras/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study. METHODS: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case. RESULTS: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. CONCLUSIONS: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.
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Proteínas Portadoras/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/fisiopatología , Niño , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Humanos , Judíos/genética , Imagen por Resonancia Magnética , Secuenciación Completa del GenomaRESUMEN
Pathogenic heterozygous variants in HMBS encoding the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase, cause acute intermittent porphyria (AIP). Biallelic variants in HMBS have been reported in a small number of children with severe progressive neurological disease and in three adult siblings with a more slowly, progressive neurological disease and distinct leukoencephalopathy. We report three further adult individuals who share a distinct pattern of white matter abnormality on brain MRI in association with biallelic variants in HMBS, two individuals with homozygous variants, and one with compound-heterozygous variants. We present their clinical and radiological features and compare these with the three adult siblings previously described with leukoencephalopathy and biallelic HMBS variants. All six affected individuals presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. This recognizable pattern of MRI abnormalities is seen in all six adults described here. Biallelic variants in HMBS cause a phenotype that is distinct from AIP. It is not known whether AIP treatments benefit individuals with HMBS-related leukoencephalopathy. One individual reported here had improved neurological function for 12 months following liver transplantation followed by decline and progression of disease.
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Disfunción Cognitiva/genética , Hidroximetilbilano Sintasa/genética , Leucoencefalopatías/genética , Porfiria Intermitente Aguda/genética , Adulto , Alelos , Niño , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Femenino , Homocigoto , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación/genética , Fenotipo , Porfiria Intermitente Aguda/diagnóstico por imagen , Porfiria Intermitente Aguda/patologíaRESUMEN
OBJECTIVE: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. METHODS: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. RESULTS: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. CONCLUSIONS: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.
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Polymicrogyria is a malformation of cortical development characterized by overfolding and abnormal lamination of the cerebral cortex. Manifestations include epilepsy, speech disturbance and motor and cognitive disability. Causes include acquired prenatal insults and inherited and de novo genetic variants. The proportion of patients with polymicrogyria and a causative germline or mosaic variant is not known. The aim of this study was to identify the monogenic causes of polymicrogyria in a heterogeneous cohort of patients reflective of specialized referral services. Patients with polymicrogyria were recruited from two clinical centres in Australia and Belgium. Patients with evidence of congenital cytomegalovirus infection or causative chromosomal copy number variants were excluded. One hundred and twenty-three patients were tested using deep sequencing gene panels including known and candidate genes for malformations of cortical development. Causative and potentially causative variants were identified and correlated with phenotypic features. Pathogenic or likely pathogenic variants were identified in 25/123 (20.3%) patients. A candidate variant was identified for an additional patient but could not be confirmed as de novo, and therefore it was classified as being of uncertain significance with high clinical relevance. Of the 22 dominant variants identified, 5 were mosaic with allele fractions less than 0.33 and the lowest allele fraction 0.09. The most common causative genes were TUBA1A and PIK3R2. The other eleven causative genes were PIK3CA, NEDD4L, COL4A1, COL4A2, GPSM2, GRIN2B, WDR62, TUBB3, TUBB2B, ACTG1 and FH. A genetic cause was more likely to be identified in the presence of an abnormal head size or additional brain malformations suggestive of a tubulinopathy, such as dysmorphic basal ganglia. A gene panel test provides greater sequencing depth and sensitivity for mosaic variants than whole exome or genome sequencing but is limited to the genes included, potentially missing variants in newly discovered genes. The diagnostic yield of 20.3% indicates that polymicrogyria may be associated with genes not yet known to be associated with brain malformations, brain-specific somatic mutations or non-genetic causes.
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OBJECTIVE: To determine whether specific speech, language, and oromotor profiles are associated with different patterns of polymicrogyria, we assessed 52 patients with polymicrogyria using a battery of standardized tests and correlated findings with topography and severity of polymicrogyria. METHODS: Patients were identified via clinical research databases and invited to participate, irrespective of cognitive and verbal language abilities. We conducted standardized assessments of speech, oromotor structure and function, language, and nonverbal IQ. Data were analyzed according to normative assessment data and descriptive statistics. We conducted a correlation analysis between topographic pattern and speech and language findings. RESULTS: Fifty-two patients (33 male, 63%) were studied at an average age of 12.7 years (range 2.5-36 years). All patients had dysarthria, which ranged from mild impairment to anarthria. Developmental speech errors (articulation and phonology), oral motor structure and function deficits, and language disorder were frequent. A total of 23/29 (79%) had cognitive abilities in the low average to extremely low range. In the perisylvian polymicrogyria group (36/52), speech, everyday language, and oral motor impairments were more severe, compared to generalized (1 patient), frontal (3), polymicrogyria with periventricular nodular heterotopia (3), parasagittal parieto-occipital (1), mesial occipital (1), and other (7) patterns. CONCLUSIONS: Dysarthria is a core feature of polymicrogyria, often accompanied by receptive and expressive language impairments. These features are associated with all polymicrogyria distribution patterns and more severe in individuals with bilateral polymicrogyria, particularly in the perisylvian region.
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Disartria/etiología , Trastornos del Desarrollo del Lenguaje/etiología , Polimicrogiria/complicaciones , Polimicrogiria/patología , Adolescente , Adulto , Niño , Preescolar , Disartria/patología , Femenino , Humanos , Trastornos del Desarrollo del Lenguaje/patología , Imagen por Resonancia Magnética , Masculino , Adulto JovenRESUMEN
Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.
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Exoma , Pruebas Genéticas , Adolescente , Adulto , Anciano , Australia , Niño , Biología Computacional , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Prospectivos , Adulto JovenRESUMEN
Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.
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Homocigoto , Proteínas del Tejido Nervioso/genética , Trastornos del Neurodesarrollo/genética , Empalme del ARN , Proteínas de Transporte Vesicular/genética , Niño , Preescolar , Codón sin Sentido , Exoma , Exones , Femenino , Humanos , Masculino , Microcefalia/genética , Trastornos del Neurodesarrollo/diagnóstico por imagen , Linaje , Sitios de Empalme de ARN , SíndromeRESUMEN
Chudley-McCullough syndrome, a rare autosomal recessive disorder due to pathogenic variants in the GPSM2 (G-protein signaling modulator 2) gene, is characterized by early-onset sensorineural deafness and a typical combination of brain malformations, including ventriculomegaly, (partial) agenesis of the corpus callosum, cerebellar dysplasia, arachnoid cysts, frontal subcortical heterotopia, and midline polymicrogyria. When hearing loss is managed early, most patients have minor or no impairment of motor and cognitive development, despite the presence of brain malformations. We report 2 cases of Chudley-McCullough syndrome, one presenting with congenital deafness and normal development except for speech delay and one presenting prenatally with ventriculomegaly and an atypical postnatal course characterized by epileptic spasms, deafness, and moderate intellectual disability. These highlight the challenges faced by clinicians when predicting prognosis based on pre- or postnatal imaging of brain malformations. We have also reviewed the phenotype and genotype of previous published cases to better understand Chudley-McCullough syndrome.
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Agenesia del Cuerpo Calloso/diagnóstico , Agenesia del Cuerpo Calloso/patología , Quistes Aracnoideos/diagnóstico , Quistes Aracnoideos/patología , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/patología , Adolescente , Agenesia del Cuerpo Calloso/genética , Quistes Aracnoideos/genética , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Niño , Sordera/genética , Sordera/patología , Diagnóstico Diferencial , Femenino , Pérdida Auditiva Sensorineural/genética , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
BACKGROUND: Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases. METHODS: We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4-13 months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9-18 months considered all disease-associated genes. At 25-34 months we reviewed all cases and the strategies which solved them. RESULTS: Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty-seven peer-reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15% and median reanalysis timeframe of 22 months. CONCLUSION: Our findings suggest that an interval of greater than 18 months from the original report may be optimal for reanalysis. We also recommend a multi-faceted strategy for cases remaining unsolved after singleton ES.
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Secuenciación del Exoma/normas , Pruebas Genéticas/normas , Enfermedades Raras/genética , Análisis de Secuencia de ADN/normas , Pruebas Genéticas/métodos , Humanos , Enfermedades Raras/diagnóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/métodos , Secuenciación del Exoma/métodosRESUMEN
PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.
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Anomalías del Ojo , Enfermedades Hereditarias del Ojo , Proteínas ADAMTS , Segmento Anterior del Ojo , Citocromo P-450 CYP1B1/genética , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Enfermedades Hereditarias del Ojo/diagnóstico , Enfermedades Hereditarias del Ojo/genética , Factores de Transcripción Forkhead/genética , Humanos , Mutación , LinajeRESUMEN
We present the case of a male infant with bilateral perisylvian polymicrogyria associated with a de novo duplication of chromosome region 17p13.3p13.2. To our knowledge, this is the first report of polymicrogyria associated with the 17p13.3 contiguous gene duplication syndrome. Testing for known monogenic causes of polymicrogyria was negative and there was no clinical evidence of an acquired prenatal cause. Given the critical, dose-sensitive role that the 17p13.3 region plays in brain development, we suggest that the chromosome duplication is the most likely explanation for the polymicrogyria. Clinical and functional studies have demonstrated deleterious effects of increased LIS1 expression on the developing brain and the contribution of YWHAE to the brain phenotype of the 17p13 duplication syndrome. There is also evidence that CRK, the other candidate gene in this region, via interaction with LIS1, plays a critical role in cortical development. In addition to LIS1, YWHAE and CRK, our patient's chromosome duplication involves at least 100 other genes, less than half of which are annotated at the time of writing. It is expected that the ongoing use of chromosome microarray and next-generation sequencing to investigate the genetic causes of brain malformations will continue to extend our understanding of the 17p13 region and of the contributions of the genes in this region to cortical development.
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Duplicación Cromosómica , Cromosomas Humanos Par 17/genética , Polimicrogiria/genética , Polimicrogiria/patología , Humanos , Lactante , Masculino , FenotipoRESUMEN
RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher-facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Using whole-exome and ultra-deep amplicon sequencing and comparing genomic data of affected and unaffected areas of the skin, we discovered that all four individuals carried the identical RHOA missense variant, c.139G>A; p.Glu47Lys, in a postzygotic state. Molecular modeling and in silico analysis of the affected p.Glu47Lys residue in RHOA indicated that this exchange is predicted to specifically alter the interaction of RHOA with its downstream effectors containing a PKN-type binding domain and thereby disrupts its ability to activate signaling. Our findings indicate that the recurrent postzygotic RHOA missense variant p.Glu47Lys causes a specific mosaic disorder in humans.
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Alelos , Codón , Estudios de Asociación Genética , Variación Genética , Placa Neural/metabolismo , Fenotipo , Proteína de Unión al GTP rhoA/genética , Adolescente , Adulto , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética , Modelos Moleculares , Placa Neural/anomalías , Placa Neural/embriología , Conformación Proteica , Relación Estructura-Actividad , Adulto Joven , Proteína de Unión al GTP rhoA/químicaRESUMEN
The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.
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Alelos , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/genética , Flavoproteínas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Monoéster Fosfórico Hidrolasas/genética , Niño , Preescolar , Análisis Mutacional de ADN , Enfermedades Desmielinizantes/metabolismo , Fibroblastos/metabolismo , Genotipo , Humanos , Patrón de Herencia , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Linaje , FenotipoRESUMEN
Polymicrogyria (PMG) is one of the most common malformations of cortical development. It is characterized by overfolding of the cerebral cortex and abnormal cortical layering. It is a highly heterogeneous malformation with variable clinical and imaging features, pathological findings, and etiologies. It may occur as an isolated cortical malformation, or in association with other malformations within the brain or body as part of a multiple congenital anomaly syndrome. Polymicrogyria shows variable topographic patterns with the bilateral perisylvian pattern being most common. Schizencephaly is a subtype of PMG in which the overfolded cortex lines full-thickness clefts connecting the subarachnoid space with the cerebral ventricles. Both genetic and non-genetic causes of PMG have been identified. Non-genetic causes include congenital cytomegalovirus infection and in utero ischemia. Genetic causes include metabolic conditions such as peroxisomal disorders and the 22q11.2 and 1p36 continguous gene deletion syndromes. Mutations in over 30 genes have been found in association with PMG, especially mutations in the tubulin family of genes. Mutations in the (PI3K)-AKT pathway have been found in association PMG and megalencephaly. Despite recent genetic advances, the mechanisms by which polymicrogyric cortex forms and causes of the majority of cases remain unknown, making diagnostic and prenatal testing and genetic counseling challenging. This review summarizes the clinical, imaging, pathologic, and etiologic features of PMG, highlighting recent genetic advances.