Bilateral Perisylvian Polymicrogyria Research Articles

X-Linked Bilateral Polymicrogyria With Epilepsy andIntellectual Disability Associated With a Novel KIF4A Variant.

We studied three brothers and a maternal half-brother featuring global developmental delay, mild to moderate intellectual disability, epilepsy, microcephaly, and strabismus. All had bilateral perisylvian and perirolandic polymicrogyria, while some also had malformations of the hippocampus (malrotation and dysplasia), cerebellum (heterotopias and asymmetric aplasia), corpus callosum dysgenesis, and brainstem asymmetric dysplasia. Exome sequencing showed that all four patients had a novel variant (c.1597C>T:p.Leu533Phe) on the KIF4A gene on chromosome X. We discuss how this variant is possibly pathogenic and could explain the reported phenotype.

Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children

BackgroundPallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population.ResultsThirty-one individuals were enrolled (17 females/14 males; age range 0.1–17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14.ConclusionsBrain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

Heterogeneous genetic patterns in bilateral perisylvian polymicrogyria: insights from a Finnish family cohort.

Bilateral perisylvian polymicrogyria is the most common form of regional polymicrogyria within malformations of cortical development, constituting 20% of all malformations of cortical development. Bilateral perisylvian polymicrogyria is characterized by an excessive folding of the cerebral cortex and abnormal cortical layering. Notable clinical features include upper motoneuron dysfunction, dysarthria and asymmetric quadriparesis. Cognitive impairment and epilepsy are frequently observed. To identify genetic variants underlying bilateral perisylvian polymicrogyria in Finland, we examined 21 families using standard exome sequencing, complemented by optical genome mapping and/or deep exome sequencing. Pathogenic or likely pathogenic variants were identified in 5/21 (24%) of families, of which all were confirmed as de novo. These variants were identified in five genes, i.e. DDX23, NUS1, SCN3A, TUBA1A and TUBB2B, with NUS1 and DDX23 being associated with bilateral perisylvian polymicrogyria for the first time. In conclusion, our results confirm the previously reported genetic heterogeneity of bilateral perisylvian polymicrogyria and underscore the necessity of more advanced methods to elucidate the genetic background of bilateral perisylvian polymicrogyria.

Chronic traumatic encephalopathy-neuropathologic change in a routine neuropathology service: 7-year follow-up.

To follow our 2016 study of chronic traumatic encephalopathy neuropathologic change (CTE-NC) in our forensic autopsy service, we prospectively screened all cases with clinical histories of multiple concussions, persistent post-head injury symptoms, or ≥3 hospital investigations for head injuries from 2016 to 2022 inclusive using hyperphosphorylated tau (p-tau) immunostaining. The cases had routine brain sampling plus 4-6 additional lateral hemisphere samples. When "pathognomonic" CTE-NC lesions were identified, additional p-tau immunostaining was done for CTE-NC staging. Of ∼1100 adult brains aged 18-65 years examined, 85 were screened, and 16 were positive for CTE-NC (2 women, 14 men, ages 35-61 years, median 47 years). Alcohol abuse was documented in 14 of 16 (8 in combination with other substances); 5 had developmental brain anomalies (2 presumed genetic, 3 from acquired perinatal insults). Widespread p-tau deposits (high CTE-NC) were found in 7 of 16. Old brain contusions were present in 9 of 16, but CTE-NC did not colocalize. Of particular interest were (1) a man with FGFR3 mutation/hypochondroplasia and life-long head banging, (2) a woman with cerebral palsy and life-long head banging, and (3) a man with bilateral peri-Sylvian polymicrogyria, alcohol abuse, and multiple head injuries. Thus, CTE-NC occurs in association with repeated head trauma outside contact sports. Substance abuse is a common determinant of risk behavior. The utility of diagnosing mild-/low-stage CTE-NC in this population remains to be determined.

Teaching NeuroImage: Drug Refractory Epilepsy With Developmental Dysarthria Due to Bilateral Perisylvian Polymicrogyria.

A 15-year-old boy presented with 5 years of refractory focal seizures with 4–6 episodes per day. The seizure semiology was described as numbness of the left half of the body followed by tonic posturing and head version to left with loss of awareness lasting for 30 seconds. Additional symptoms included cognitive impairment with delayed and dysarthric speech. Neuropsychological assessment revealed impaired intellectual and cognitive ability. MRI of the brain demonstrated bilateral perisylvian polymicrogyria (Figure, A–C). BPP is a cortical development malformation1 characterized by widened Sylvian fissures with an increased number of abnormally small gyri and shallow sulci. Patients present with dysarthria and refractory seizures.2

Bilateral Perisylvian Polymicrogyria in Infant Revealed by Status Epilepticus

Polymicrogyria is a malformation characterized by an abnormality in late neuronal migration and cortical organization, that causes usually recurrent seizures and or status epilepticus. It results from a combination of genetic and non-genetic factors. We report a case of bilateral perisylvian polymicrogyria in an infant with status epilepticus.

Uncommon variants of speech disorder in children: congenital bilateral perisylvian syndrome

This paper describes two cases of congenital bilateral perisylvian syndrome (CBPS), a rare disorder of late neuronal migration, which is characterized by language delay, intellectual disorders, epilepsy and bilateral perisylvian polymicrogyria. Pseudobulbar paralysis and orofacial muscles dyspraxia causing drooling and feeding difficulties are common for patients with CBPS. Communicational problems lead to low self-esteem and social maladaptation. Literature data regarding correlation between polymicrogyria topography and speech disorders and articulation impairment severity are presented. The results demonstrate the association of diffuse spreading of bilateral polymicrogyria and more severe speech disorders comparing to mild speech disorders in patients with more local polymicrogyria. Known etiology factors of this syndrome are bilateral cerebral hypoperfusion, brain damage while neuronal migration period, postmigrational vascular insults and gene mutations. Syndrome can be inherited in autosome dominant and X-linked manner. Speech apraxia with normal impressive speech, refractory epileptic seizures and status dysraphicus must be red flags for a physician regarding this syndrome. Overnight video-EEG monitoring and brain MRI confirm a thesis that this syndrome is underdiagnosed in everyday clinical practice.

A-64 Neuropsychological Assessment in Bilateral Perisylvian Polymicrogyria: A Tool for Data-Driven Intervention

Abstract Objective This case study examined neurocognitive features associated with a rare genetic/neurological disorder impacting the cerebral cortex. Bilateral perisylvian polymicrogyria (BPP) is characterized by abnormal embryonic growth affecting both sides of the brain near the Sylvian fissure. BPP occurs randomly though researchers suspect an underlying genetic abnormality that may have autosomal recessive inheritance. Neurodevelopmental manifestations include neurocognition marked by EEG abnormalities, impaired motor function, and deficits in speech articulation, language development, learning and memory, and adaptive skills. Method A 13-year 7-month-old male with BPP, detected at 24 months by MRI, was seen for neuropsychological assessment to guide habilitative, academic and adaptive interventions. Relevant medical history includes stimulant medication and pharyngeal flap surgery. Parental concerns include the provision of appropriate special education services and withdrawal behaviors. Results Assessment revealed a complex neuropsychological profile characterized by nonverbal versus verbal intellectual strengths, receptive-expressive language impairment, underlying deficits in phonemic awareness, diminished fine motor speed, and diminished verbal fluency. Verbal list learning, semantic memory, and attention were intact. Mild elevations were evident for anxiety symptoms. Conclusion BPP, a rare genetic disorder, represents significant challenges for affected children. In this case study, a 13-year 7-month-old youngster’s assessment revealed underlying neurocognitive and neuromotor deficits most pronounced in aspects of language, speech articulation, select domains of executive functioning and academic skills. Areas of strength, including verbal memory and semantic recall, were indicated and merit consideration in developing appropriate interventions. This case study illustrates the value of neuropsychological assessment in guiding therapeutic interventions, pharmacotherapy, and appropriate educational services in this rare neurological disorder.

Symptomatic eating epilepsy: two novel pediatric patients and review of literature

Eating epilepsy (EE) is a form of reflex epilepsy in which seizures are triggered by eating. It is a rare condition but a high prevalence has been reported in Sri Lanka. In EE, the ictal semiology includes focal seizures with or without secondary generalization or generalized seizures. Some cases are idiopathic while focal structural changes on imaging, if present, are often confined to the temporal lobe or perisylvian region. On the other hand, some cases support the hypothesis of a genetic aetiology. The prognosis of EE is extremely variable due to the different nature of the underlying disorder. We describe two patients with symptomatic eating epilepsy, a 13-year-old boy with a bilateral perisylvian polymicrogyria and a 2-year-old boy with a genetic cause. The presence of structural lesions or the dysfunction of specific cortical regions in the context of a germline genetic alteration might lead to a hyperexcitation fostering the epileptogenesis. We review the available literature to clarify the aetiopathogenesis and the mechanisms underlying EE to improve the diagnosis and the management of these rare conditions.

Diverse genetic causes of polymicrogyria with epilepsy.

We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy. We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA. Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus. This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.

Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding.

Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) is an extremely rare autosomal recessive genetic disorder caused by variants in the MED25 gene. It is characterized by severe developmental delay and variable craniofacial, neurological, ocular, and cardiac anomalies. Since 2015, through whole exome sequencing, 20 patients have been described with common clinical features and biallelic variants in MED25, leading to a better definition of the phenotype associated with BVSYS. We report two young sisters, born to consanguineous parents, presenting with intellectual disability, neurological findings, and dysmorphic features typical of BVSYS, and also with bilateral perisylvian polymicrogyria. The younger sister died at the age of 1year without autoptic examination. Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs). This report further delineates the most common clinical features of BVSYS and points to polymicrogyria as a distinctive neuroradiological feature of this syndrome.

Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.

Four patients with D-bifunctional protein (DBP) deficiency: Expanding the phenotypic spectrum of a highly variable disease

IntroductionPeroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder historically described as a Zellweger-like syndrome comprising neonatal seizures, retinopathy, hearing loss, dysmorphic features, and other complications. The HSD17B4 gene encodes DBP which is essential for oxidation of peroxisomal substrates. We describe 4 patients - 2 unrelated female girls and 2 monozygotic twin sisters - with DBP deficiency and phenotypic diversity. Patient reportsPatient 1 presented neonatally with hypotonia and seizures, and later on developed global developmental delay and regression, sensorineural hearing loss, nystagmus and cortical blindness. The brain MRI demonstrated bilateral peri-sylvian polymicrogyria. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.752G>A, p.(Arg251Gln); c.868 + 1delG).Patient 2 presented with hypotonia, motor delay, and sensorineural hearing loss in infancy, considerable developmental regression during her fourth year, nystagmus, and peripheral neuropathy. Brain MRI demonstrated cerebellar atrophy and abnormal basal ganglia and white matter signal, which appeared after the age of two years. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.14 T>G, p.(Leu5Arg); c.752G>A, p.(Arg251Gln)).Patients 3 and 4, two female monozygotic twins, presented with hypotonia, developmental delay, and macrocephaly from birth, and later on also sensorineural hearing loss, infantile spasms and hypsarrhythmia, and adrenal insufficiency. Brain MRI demonstrated delayed myelination, and an assay of peroxisomal beta oxidation suggested DBP deficiency. Sequencing of the HSD17B4 gene revealed the same 2 mutations as in patient 1. DiscussionWe describe 4 patients with variable and diverse clinical picture of DBP deficiency and particularly emphasize the clinical, biochemical, and neuroimaging characteristics. Interestingly, the clinical phenotype varied even between patients with the exact two mutations in the HSD17B4 gene. In addition, in two of the three patients in whom levels of VLCFA including phytanic acid were measured, the levels were within normal limits. This is expanding further the clinical spectrum of this disorder, which should be considered in the differential diagnosis of every patient with hypotonia and developmental delay especially if accompanied by polymicrogyria, seizures, sensorineural hearing loss, or adrenal insufficiency regardless of their VLCFA profile.

Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Previously reported AKT3 variants are associated with various brain abnormalities and may lead to megalencephaly. MPPH syndrome is usually due to germline pathogenic AKT3 variants. Somatic mosaic pathogenic variants associated with hemimegalencephaly, which is similar to MPPH, have also been observed. A Hungarian Roma family with two half-siblings, which present with intellectual disability, dysmorphic features, epilepsy, brain malformations, and megalencephaly was studied. Whole exome sequencing (WES) analysis was performed. WES analysis revealed a heterozygous c.1393C > T p.(Arg465Trp) pathogenic missense AKT3 variant in both affected half-siblings. The variant was verified via Sanger sequencing and was not present in the DNA sample from the healthy mother, which was derived from peripheral blood, suggesting maternal germline mosaicism. In conclusion, this is the first report in which maternal germline mosaicism of a rare pathogenic AKT3 variant leads to autosomal dominantly inherited MPPH syndrome.

Septopreoptic holoprosencephaly in intracranial abnormalities: an under-diagnosed midline finding.

Septopreoptic holoprosencephaly is a mild form of holoprosencephaly in which the midline non-separation is restricted to the septal or preoptic regions. This entity has only been described in a small case series in which associated intracranial abnormalities were limited to the midline structures. To describe the radiologic findings of septopreoptic holoprosencephaly and highlight that it can be associated with a variety of intracranial abnormalities, not merely with abnormalities restricted to midline structures as previously reported. We retrospectively identified 22 children whose MRIs were confirmed to have non-separation restricted to the septal and preoptic region, fulfilling the criteria for septopreoptic holoprosencephaly. We then categorized MRIs as having, in addition, either intracranial abnormalities limited to the midline structures or major abnormalities not limited to the midline structures. Five children had intracranial abnormalities limited to the midline structures. Seventeen children had major intracranial abnormalities not limited to the midline structures. The major abnormalities included: patterning defects of the midbrain-hindbrain (elongated midbrain, shortened pons, shortened/elongated medulla, partial rhombencephalosynapsis), bilateral perisylvian polymicrogyria, microcephaly, megalencephaly and a spheno-ethmoidal encephalocele. Recognized syndromes/chromosomal abnormalities were also observed in this patient group. Our results suggest that septopreoptic holoprosencephaly has been under-recognized and under-reported to date. We propose that searching for this anomaly should be part of the complete assessment of the midline in all children undergoing brain MRI for intracranial malformations.

Polymicrogyria associated with 17p13.3p13.2 duplication: Case report and review of the literature

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.

SCN2A mutation in an infant with Ohtahara syndrome and neuroimaging findings: expanding the phenotype of neuronal migration disorders

Neuronal migration disorders (NMDs) are a heterogeneous group of conditions caused by the abnormal migration of neuroblasts in the developing brain and nervous system, resulting in severe developmental impairment, intractable epilepsy and intellectual disability (Spalice et al. 2009). To date, many genes have been identified as the leading cause of migration defects, i.e. agyria/pachygyria, polymicrogyria, heterotopias, agenesis of the corpus callosum and agenesis of the cranial nerves (Spalice et al. 2009). Here, we present a patient with early infantile epileptic encephalopathy (Ohtahara syndrome) with seizure onset on the first dayof life, severe developmental delay and an abnormal brain MRI with excessive folding of small, fused gyri and bilateral perisylvian polymicrogyria, suggestive of neuronal migration disorder. To clarify the unknown aetiology, we conducted whole-exome sequencing, which detected a de novo missense variant (c.5308A>T; p.(Met1770Leu)) in the SCN2A gene. This is a report of SCN2A gene variant identified in a patient with neuronal migration disorder which could further expand the phenotypic spectrum of these genetic disorders.

Speech and language in bilateral perisylvian polymicrogyria: a systematic review

We aimed to systematically review the speech production, language, and oral function phenotype of bilateral perisylvian polymicrogyria (BPP), and examine the correlation between the topography of polymicrogyria and the severity of speech, language, and oral functional impairment. A systematic search of MEDLINE, Embase, and PubMed databases was completed on 26th October 2017 using Medical Subject Heading terms synonymous with BPP and speech, language, or oral motor impairment. In total, 2411 papers were identified and 48 met inclusion criteria. Expressive and receptive language impairment and oral structural and functional deficits are frequent in BPP. Expressive deficits are frequently more severe than receptive. Only one study used formal assessments to demonstrate the presence of speech disorder, namely dysarthria. Seven studies reported an association between diffuse BPP and more severe language impairment. Findings confirmed that language deficits are common in BPP, though assessment of the specific speech phenotype is limited. The paucity of high quality studies detailing the specific communication phenotype of BPP highlights the need for further investigation. Improving understanding of this phenotype will inform the development of targeted therapies and lead to better long-term outcomes. Speech, language, and oral functional impairments are common in individuals with bilateral perisylvian polymicrogyria. Posterior polymicrogyria is associated with a less severe language impairment than anterior polymicrogyria. Deeper investigation of speech is needed to understand implicated networks in this malformation.

Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation.

The TUBA1A gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in TUBA1A have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in TUBA1A, c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations.

Chromothripsis and ring chromosome 22: a paradigm of genomic complexity in the Phelan-McDermid syndrome (22q13 deletion syndrome)

IntroductionPhelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly...