Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.
...Clinical phenotyping, targeted or exome sequencing, and autozygome analysis.
We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.
Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.
Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and ...Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.
To investigate the utility of autozygome analysis and exome sequencing in a cohort of patients with suspected or confirmed mitochondrial encephalomyopathy.
Autozygome was used to highlight candidate ...genes for direct sequencing in 10 probands, all born to consanguineous parents. Autozygome was also used to filter the variants from exome sequencing of four probands.
In addition to revealing mutations in known mitochondrial genes, the analysis revealed the identification of two novel candidate disease genes: MFF and FARS2, encoding the mitochondrial fission factor and phenylalanyl-tRNA synthetase, respectively.
These findings expand the repertoire of genes that are mutated in patients with mitochondrial disorders and highlight the value of integrating genomic approaches in the evaluation of these patients.
Klippel-Feil anomaly (KFA) can be seen in a number of syndromes. We describe an apparently novel syndromic association with KFA.
Clinical phenotyping of two consanguineous families followed by ...combined autozygome/exome analysis.
Two patients from two apparently unrelated families shared a strikingly similar phenotype characterised by KFA, myopathy, mild short stature, microcephaly, and distinctive facies. They shared a single founder autozygous interval in which whole exome sequencing revealed a truncating mutation in MYO18B. There was virtually complete loss of the transcript in peripheral blood, indicative of nonsense-mediated decay. Electron microscopy of muscle confirms abnormal myosin filaments with accompanying myopathic changes.
Deficiency of MYO18B is linked to a novel developmental disorder which combines KFA with myopathy. This suggests a widespread developmental role for this gene in humans, as observed for its murine ortholog.
Ehlers–Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical ...manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes
B3GALT6
,
GORAB
,
ZNF469
,
B3GAT3
,
ALDH18A1
,
FKBP14
,
PYCR1
,
CHST14
and
SPARC
with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive
COL1A1
variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene,
AEBP1
. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose
ATP6V1E1
and
ATP6V0D2
(two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.
Epileptic encephalopathy is a broad clinical category that is highly heterogeneous genetically.
To describe a multiplex extended consanguineous family that defines a molecularly novel subtype of ...early infantile epileptic encephalopathy.
Autozygosity mapping and exome sequencing for the identification of the causal mutation. This was followed by expression analysis of the candidate gene.
In an extended multigenerational family with six affected individuals, a single novel disease locus was identified on chromosome 12p13.31-p13.2. Within that locus, the only deleterious novel exomic variant was a homozygous truncating mutation in NECAP1, encoding a clathrin-accessory protein. The mutation was confirmed to trigger nonsense-mediated decay. Consistent with previous reports, we show that NECAP1 is highly enriched in the central nervous system.
NECAP1 is known to regulate clathrin-mediated endocytosis in synapses. The mutation we report here links for the first time this trafficking pathway in early infantile epileptic encephalopathy.
Brown-Vialetto-Van Laere (BVVL) syndrome is an extremely rare autosomal recessive progressive motoneuron disease that is caused by a defect in the riboflavin transporter genes SLC52A2 and SLC52A3. ...BVVL syndrome has a variable age of presentation, and it is characterized by progressive auditory neuropathy, bulbar palsy, stridor, muscle weakness, and respiratory compromise secondary to diaphragmatic and vocal cord paralysis. BVVL syndrome has a poor prognosis in the absence of treatment, including morbidity with quadriparesis and sensorineural hearing loss, with mortality in the younger age group. Early administration of riboflavin is associated with prolonged survival, low morbidity, and reversal of some clinical manifestations.
We describe an 18-month-old male infant with progressive pontobulbar palsy, loss of developmental milestones, and a clinical picture suggestive of chronic inflammatory demyelinating neuropathy. A nerve conduction study revealed axonal neuropathy, while molecular analysis revealed a homozygous mutation in one of the riboflavin transporter genes, SLC52A3, confirming BVVL syndrome. The patient needed long-term respiratory support and a gastrostomy tube to support feeding. With high-dose riboflavin supplementation, he experienced moderate recovery of motor function.
This report highlights the importance of considering BVVL syndrome in any patient who presents with the clinical phenotype of pontobulbar palsy and peripheral axonal neuropathy, as early riboflavin treatment may improve or halt disease progression, thus reducing the associated mortality and morbidity.
Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known ...disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.
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•Multiplex consanguineous families are rich sources for novel gene discovery•Prescreening these families for known disease genes accelerates gene discovery•33 novel candidate genes are reported in this study
Using whole-exome sequencing on prescreened multiplex consanguineous families, Alazami et al. describe the identification of 33 novel candidate genes for various neurogenetic conditions. Such families are rich sources for novel gene discovery.
To evaluate the electro-clinical manifestations and outcomes of children with absence epilepsy at a tertiary center in Saudi Arabia.
This retrospective study reviewed the medical and EEG records of ...patients who were diagnosed to have CAE as per the International League Against Epilepsy (ILAE) definition for CAE. The study was conducted in the pediatric neurology clinic of King Khalid University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia, between January 2000 and December 2019. Patients who did not meet (ILAE) criteria, lost follow-up, and those who did not receive treatment at KKUH were excluded. Data regarding the patient's disease, electro-clinical manifestations, anti-seizure medication response, and outcomes were collected.
A total of 35 patients, with an average age at diagnosis of 7 ± 2.1 y, were included in the study; among them, 51.4% were female and approximately 48.6% presented with a family history of epilepsy. Regarding clinical features, all patients experienced staring and altered awareness, 94.2% had less than 20 spells per day at the time of diagnosis, and 65.7% were provoked by the hyperventilation test. Regarding EEG findings, all patients had bilateral, symmetrical, and synchronous discharges in the form of regular 3 Hz spike-and-wave complexes, and 94.3% had a generalized initial ictal discharge. Also, 22.8% had eye fluttering with electrographic seizures. Ethosuximide (ESM) was used as the drug of choice in 45.7% of the patients. Regarding clinical outcomes, 94.3% had their disease clinically controlled, and 80% had a normalized EEG after few months of starting anti-seizure medication. Finally, 37.2% experienced complete remission of epilepsy after 3–5 y; however, one patient developed juvenile myoclonic epilepsy.
This study described the electro-clinical manifestations of patients with childhood absence epilepsy and outcomes. Furthermore, early diagnosis and prompt treatment of childhood absence epilepsy improve treatment outcomes.
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