A Novel Homozygous Splice Site Variant in AIMP1 Gene Causing Hypomyelinating Leukodystrophy: Case Report and Review of the Literature.

BACKGROUND: Biallelic pathogenic variants in AIMP1 gene cause hypomyelinating leukodystrophy type 3, a severe neurodegenerative disorder with early onset characterized by microcephaly, axial hypotonia, epilepsy, spasticity, and developmental delay. METHODS: Clinical exome sequence was performed on patient's DNA and Sanger sequencing was used to confirm the candidate variant. To better characterize the effect of the genetic variant, functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) was performed. RESULTS: We report a case of 2-year-old girl with microcephaly, significant global developmental delay, refractory epilepsy, flaccid paralysis, hypomyelination, leukodystrophy, and cerebral atrophy on brain magnetic resonance imaging (MRI). Clinical exome sequencing revealed a novel splice site variant c.603 + 1G > A in homozygosity in the AIMP1 gene. Studies on patient's cDNA showed that the variant disrupts the canonical donor splice site of intron 5, with the recognition of a cryptic splice site within exon 5, leading to the skipping of the last 24 nucleotides of this exon together with the flanking intron. This alteration is predicted to cause an in-frame deletion of eight amino acids (p.Val194_Gln201del) belonging to the tRNA-biding domain of the protein. CONCLUSION: To the best of our knowledge, this is the first report of a splice site variant in the AIMP1 gene causing hypomyelinating leukodystrophy. The description of this patient not only expands the mutational spectrum of AIMP1 but also provides deeper insights on genotype-phenotype correlation by comparing the clinical features of our patient with previously reported affected individuals.

Congenital heart defects associated with pathogenic variants in WAC gene: Expanding the phenotypic and genotypic spectrum of DeSanto-Shinawi syndrome.

WAC-related intellectual disability, also known as DeSanto-Shinawi syndrome, is a rare autosomal dominant genetic disorder caused by pathogenic variants in WAC gene. This syndrome is characterized by developmental delay, intellectual disability, behavioral abnormalities, and dysmorphic facial features, including deep-set eyes, flat nasal bridge, bulbous nasal tip, and synophrys. Chromosomal deletions at 10p12p11 encompassing WAC gene have been described in patients with a similar phenotype, presenting with developmental delay, intellectual disability, visual impairments, abnormal behavior, and dysmorphic features. An important clinical difference between the two groups of patients, is that those with large deletions frequently present with congenital cardiac defects, which were rarely reported in patients with pathogenic variants in WAC. The genes underlying heart defects in patients with the deletion have not yet been fully clarified. Here, we describe two unrelated Portuguese patients with de novo pathogenic variants in WAC gene, previously unreported in the literature. Both patients present with microcephaly, developmental delay, intellectual disability, behavioral problems, and facial dysmorphisms. Interestingly, the youngest patient has a severe congenital cardiac malformation, showing that intragenic pathogenic WAC variants can also be associated with heart defects. Therefore, this report expands the phenotypic and genotypic spectrum of this rare syndrome and provides deeper insights by comparing the clinical features of our patients with previously reported cases.

Expanding the Phenotypic Spectrum of HIVEP2-Related Intellectual Disability: Description of Two Portuguese Patients and Review of the Literature.

Introduction: Pathogenic variants in HIVEP2 have been associated with a neurodevelopmental disorder mainly characterized by intellectual disability, severe language impairment, and motor developmental delay. Since its first description in 2016, only 15 patients have been described in the literature. Methods: Here, we report 2 additional unrelated Portuguese children presenting intellectual disability and motor delay in whom de novo nonsense pathogenic variants in HIVEP2 have been identified by next-generation sequencing analysis. Results: In patient 1, the variant c.2827C>T, p.(Arg943*) was detected, whereas patient 2 carried the variant c.6667C>T, p.(Arg2223*). Interestingly, patient 1 presented with a rapid growth of the occipitofrontal diameter in the first months of life due to external hydrocephalus, a feature that, as far as we know, has never been reported in patients with HIVEP2 pathogenic variants. Conclusion: This report expands the phenotypic spectrum of this rare syndrome and provides deeper insights by comparing the clinical features of our patients with previously reported affected individuals.

Symptomatic hypoglycemia in a child with common variable immunodeficiency: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome.

Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a rare condition characterized by symptomatic ACTH deficiency and primary hypogammaglobulinemia, caused by pathogenic variants of the nuclear factor kappa-B subunit 2 (NF-κB2) gene. We report the case of a 9-yr-old boy diagnosed with common variable immunodeficiency at the age of 3, who is under monthly intravenous immunoglobulin. The patient was admitted twice to the pediatric emergency service at the age of 9 due to symptomatic hypoglycemic events. During the hypoglycemic crisis, serum cortisol was low (< 0.1 µg/dL), ACTH level was inappropriately low (4.4 ng/L) and the ACTH stimulation test failed to raise the blood cortisol level. Pituitary magnetic resonance imaging showed a hypoplastic pituitary. Other pituitary deficiencies, primary hyperinsulinism and other metabolic diseases were excluded. He started hydrocortisone replacement treatment while maintaining immunoglobulin substitution and he remains asymptomatic. Molecular analysis revealed the heterozygous nonsense pathogenic variant, c.2557C>T (Arg853Ter) in the NF-κB2 gene. Thus, symptomatic hypoglycemia in a child with primary immunodeficiency should raise the suspicion of DAVID syndrome, prompting NF-κB2 molecular analysis, to allow timely and appropriated therapy and genetic counseling.

VRK1 variants in two Portuguese unrelated patients with childhood-onset motor neuron disease.

VRK1 encodes a serine/protein kinase possibly involved in pathways related to amyotrophic lateral sclerosis (ALS) pathogenesis. Pathogenic variants in VRK1 have been related to different phenotypes. We describe the clinical phenotype of two unrelated Portuguese patients with different VRK1 variants. Both patients presented a bilateral distal weakness in lower limbs beginning in childhood slowly progressing to upper limbs, associated with pyramidal signs, without bulbar, respiratory or cognitive involvement, according to probable ALS. Imaging and nerve conduction studies were unremarkable in both patients. Genetic testing in patient 1 identified two VRK1 variants in heterozygosity: c.265C > T, p.(Arg89*) and c.769G > A, p.(Gly257Ser), classified as pathogenic and variant of uncertain significance, respectively. In patient 2, two probably pathogenic variants in VRK1 were identified in heterozygosity: c.710-14T > C in intron 8 and c.721C > T, p.(Arg241Cys) in exon 9. We report two unrelated patients with different variants in VRK1 displaying a similar childhood-onset motor neuron disease/ALS, further expanding the phenotypic spectrum associated to VRK1 variants.

12q14 microduplication: a new clinical entity reciprocal to the microdeletion syndrome?

BACKGROUND: 12q14 microdeletion syndrome is characterized by low birth weight and failure to thrive, proportionate short stature and developmental delay. The opposite syndrome (microduplication) has not yet been characterized. Our main objective is the recognition of a new clinical entity - 12q14 microduplication syndrome. - as well as confirming the role of HMGA2 gene in growth regulation. CASE PRESENTATION: Array Comparative Genomic Hybridization (CGH), Karyotype, Fluorescence in situ Hybridization, Quantitative-PCR analysis and Whole exome sequencing (WES) were performed in a girl presenting overgrowth and obesity. Array CGH identified a 1.5 Mb 12q14.3 microduplication involving HMGA2, GRIP1, IRAK3, MSRB3 and TMBIM4 genes. Karyotype and FISH showed that duplication was a de novo insertion of 12q14.3 region on chromosome 9p resulting in an interstitial microduplication. Q-PCR confirmed the duplication only in the proband. WES revealed no pathogenic variants. CONCLUSIONS: Phenotypic comparison with patients with 12q14 microdeletion syndrome showed a reciprocal presentation, suggesting a phenotypically recognizable 12q14 microduplication syndrome as well as confirming the role of HMGA2 gene in growth regulation. It is also indicative that other genes, such as IRAK3 and MSRB3 might have of role in weight gain and obesity.

Wiedemann-Steiner syndrome in two patients from Portugal.

Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder characterized by growth retardation, facial dysmorphism, hypertrichosis cubiti and neurodevelopment delay. It is caused by pathogenic variants in the KMT2A gene. This report describes two unrelated Portuguese patients, age 11 and 17 years, with a phenotype concordant with WSS and clinical and molecular diagnosis of WSS by the identification of two novel frameshift variants in the KMT2A gene. This work also highlights the presence of certain clinical features in patients with growth retardation and development delay and should draw attention to the diagnosis of WSS, when hirsutism, particularly hypertrichosis cubiti is present.

Chiari Malformation Type I in a Patient with a Novel NKX2-1 Mutation.

Chiari Malformation Type 1 is a congenital, condition characterized by abnormally shaped cerebellar tonsils that are displaced below the level of the foramen magnum. NKX2-1 gene encodes a transcription factor expressed during early development of thyroid, lung, and forebrain, and germline NKX2-1 mutations can lead to dysfunction in any of these three organs, resulting in brain-lung-thyroid syndrome. There have been few reports of structural brain anomalies in patients with an NKX2-1-related disorder. We report the first case of a girl with a genetically identified mutation in NKX2-1 that presents with a Chiari Malformation Type 1, eventually expanding the phenotypic spectrum of NKX2-1-related disorders while also highlighting a novel heterozygous pathogenic variant at exon 3 that disrupts the reading framework, originating an NKX2-1 protein with a different C-terminal.

Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism.

Background Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods From an initial cohort of 79 patients with permanent CH (3-19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH.

Mandibulofacial dysostosis with microcephaly: a syndrome to remember.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare condition that causes abnormalities of the head and face. Other major extracranial malformations may also be found. The authors present a case of an MFDM in a 35 weeks newborn with antenatal growth restriction. The patient required resuscitation at birth and was diagnosed with oesophageal atresia with tracheoesophageal fistula at day 1. At physical examination he presented multiple congenital malformations including prominent forehead, plagiocephaly, low-set ears, malformed auricles, hypertelorism, downward-slanting eyes, micrognathia, everted lower lip, short neck, wide-spaced nipples and inguinal hernia. Imaging investigation showed dysplasia of the inner ear with agenesis of the vestibular-cochlear nerves and global cerebral atrophy. Analysis of the EFTUD2 gene revealed that the patient was a heterozygous carrier of a pathogenic mutation (c.831_832del[p.Lys277Asnsf*7]), which has not been previously described. This case illustrates the challenges faced in diagnosing and treating MFDM patients.

Diagnostic yield of next-generation sequencing applied to neurological disorders.

The exponential knowledge on the genetic etiology and the trend towards genetically-specific therapies for previously untreatable disorders, requires neurologists to be familiar with the strengths and weaknesses of Next-Generation Sequencing (NGS). Our aim was to assess the diagnostic yield of NGS studies in clinical practice in our setting. We performed a retrospective, cross-sectional, 18 months long study, from a single Portuguese center, of consecutive neurological patients for whom a NGS study was requested. A diagnosis rate (DR) of 33.2% was achieved for a total of 190 patients (89 children). It was higher for muscle diseases (DR 61.1%). In 20%, an inconclusive molecular diagnosis was obtained. The rate of incidental findings (IF) was 5.3%. We found better DR for clinical exome (52.6%, p < 0.05) although only 14% of patients were characterized using this approach. The performance of gene panels for muscle diseases was better but not statistically significant (DR 56.3% vs. 31.7% overall, p > 0.05). The reduced number of patients in several phenotypic groups limits the interpretation of specific diagnostic yields. The better yield of gene panels for muscle diseases suggests that gene panels may be a more cost-effective first-line test in well-defined phenotypes. For heterogeneous phenotypes and overall, WES-based virtual panels or clinical exome should be favored. We present daily practice evidence that, with the constraints of our health system, for one third of the patients with neurological disorders of undetermined etiology a definitive diagnosis can be reached with NGS.

Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease.

OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation. METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge. CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Mitochondrial Encephalopathy: First Portuguese Report of a VARS2 Causative Variant.

INTRODUCTION: Combined oxidative phosphorylation deficiency 20 (COXPD20) is a mitochondrial respiratory chain complex (RC) disorder, caused by disease-causing variants in the VARS2 gene, which encodes a mitochondrial aminoacyl-tRNA synthetase. Here we describe a patient with fatal mitochondrial encephalopathy caused by a homozygous VARS2 gene missense variant. CASE REPORT: We report the case of a girl, the first child of non-consanguineous and healthy parents, born from an uneventful term pregnancy, who presented, in the neonatal period, major hypotonia and microcephaly. At 4 months of age she showed poor eye contact, nystagmus, global psychomotor development delay and failure to thrive, without dysmorphic features. Focal seizures started at 24 months which evolved to a severe epileptic encephalopathy and finally to super refractory status epilepticus, leading to her death at 28 months of age. Etiologic investigation encompassing metabolic and genetic causes failed to disclose a diagnosis. Post-mortem exome sequencing allowed the identification of a pathogenic variant in VARS2 gene in the homozygous state (c.1100C > T, p.Thr367Ile) in the patient, inherited from her heterozygous parents, leading to the diagnosis of COXPD2. CONCLUSION: To the best of our knowledge, this is the fifth case described in the literature of a child with disease-causing variant in VARS2. With this report we expand the knowledge about the phenotype associated with this very rare mitochondrial defect, further emphasizing the use of exome sequencing as a very powerful diagnostic tool.

[Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar São João, Portugal]. / Investigação de Etiologia Genética nas Ataxias Neurodegenerativas: Recomendações do Grupo de Neurogenética do Centro Hospitalar São João, Portugal.

In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar São João, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information) and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality.

Nas últimas décadas foi identificada uma lista crescente de ataxias neurodegenerativas de causa monogénica, permitindo uma melhor caracterização da patofisiologia, fenótipo e prognóstico deste grupo heterogéneos de patologias e revelando potenciais novos alvos terapêuticos. No entanto, a heterogeneidade e complexidade da relação genótipo-fenótipo e os elevados custos inerentes às técnicas de genética molecular, dificultam o plano racional clínico na orientação da investigação destas doenças. A história clínica é essencial à orientação diagnóstica, mas frequentemente o fenótipo não detém especificidade suficiente para permitir prever o genótipo. O Grupo de Neurogenética do Centro Hospitalar São João, grupo multidisciplinar de neurologistas e geneticistas com interesse especial na área das doenças neurogenéticas, delineou recomendações de consenso para a investigação da etiologia genética das ataxias neurodegenerativas, tendo por base documentos de consenso internacionais (contendo atualmente informação potencialmente desatualizada) e a evidência científica publicada sobre este tópico. Atualmente estão bem descritos aproximadamente 10 loci autossómicos recessivos e mais de 27 loci autossómicos dominantes para as ataxias neurodegenerativas. Este documento aborda de forma pragmática o processo utilizado para o diagnóstico genético das ataxias neurodegenerativas, com recomendações específicas para os diversos grupos de ataxias hereditárias e adaptado à realidade Portuguesa.

[Genetic Study of Primary Dystonias: Recommendations from the Centro Hospitalar São João Neurogenetics Group]. / Estudo Genético nas Distonias Primárias: Recomendações do Grupo de Neurogenética do Centro Hospitalar São João.

The primary dystonias are a particular group of dystonias of presumed genetic origin, with a wide age of onset and variable progression. The diagnosis is, therefore, a challenge and the issue of the genetic investigation presents frequently in clinical practice. In the past few years several gene mutations have been identified as causative of primary dystonias. The choice of molecular testing is complex, given the clinical specificities and low frequency of these entities and the cost of genetic testing. It must follow observation by specialized clinicians highly differentiated in this area and be supported by a rational plan of investigation. The Centro Hospitalar São João Neurogenetics Group, a multidisciplinary team of Neurologists and Geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic etiology of the primary dystonias, based on international consensus documents and recent published scientific evidence. This manuscript adopts the new classification system for genetic movement disorders, allowing for its systematic and standardized use in clinical practice.

As distonias primárias são um grupo particular de distonias, de etiologia presumivelmente genética e com sintomas que podem surgir em diversas idades e progredir durante um período variável de tempo. O seu diagnóstico constitui, por isso, um desafio, colocando-se frequentemente na prática clínica a questão da realização do estudo genético. Nos últimos anos foram identificadas várias mutações genéticas causadoras de distonia primária. A escolha do teste molecular é complexa, quer pela especificidade clínica e baixa frequência, quer pelo custo associado ao estudo genético. Esta escolha deve ser feita mediante observação especializada por médicos com elevada diferenciação nesta área, apoiada num plano racional de investigação. O Grupo de Neurogenética do Centro Hospitalar São João (grupo multidisciplinar de Neurologistas e Geneticistas com interesse especial na área das doenças neurogenéticas) delineou recomendações de consenso para a investigação da etiologia genética das distonias primárias, tendo por base documentos de consenso internacionais e a evidência científica entretanto publicada. Este documento adota o novo sistema de nomenclatura para as formas genéticas de doenças do movimento, permitindo a sua utilização padronizada e sistemática na prática clínica.

Torcular pseudomass: a potential diagnostic pitfall in infants and young children.

BACKGROUND: Incidental findings on brain MRI may constitute a diagnostic pitfall. We observed an incidental extra-axial midline rounded pseudomass between the torcular Herophili and the occipital squama, with spontaneous resolution, which we called "torcular pseudomass." OBJECTIVE: We investigated the frequency, imaging features, natural history and developmental background of this finding in a large group of infants and young children. MATERIALS AND METHODS: We conducted a single-center retrospective study by reviewing all brain MRIs performed in children younger than 3 years between 2007 and 2013 in a specialized pediatric hospital. We looked for soft tissue (minimum 2 mm thick) interposed between the torcula and the occipital squama on midsagittal T1 and T2 images; we recorded the maximal diameters and outcome. RESULTS: Of 2,283 the children who had brain MRIs during the study period, 291 (12.7%, 95% confidence interval [CI] 0.11, 0.14) presented with a torcular pseudomass (median age 4 months, range 0 days to 35 months, 56% male). MRI features were the same in all of these children: T1 isointensity and T2 hyperintensity to the cerebral cortex, facilitated diffusion on diffusion-weighted imaging and apparent diffusion coefficient maps, and contrast enhancement. The median diameters were: anteroposterior, 5.8 mm; transverse, 10.5 mm; cranio-caudal, 20.6 mm. Follow-up MRI was available in 34.7% (95% CI: 0.20, 0.40) of the children; median follow-up time was 18 months. Among these children, 35.6% (95% CI: 0.26, 0.45) had total involution, 52.5% (95% CI: 0.26, 0.62) had partial involution and 4.1% (95% CI: 0.05, 0.18) showed stability. CONCLUSION: Redundant soft tissue in the torcular region, or torcular pseudomass, is not an infrequent finding in infants and young children. It should be considered a physiological tissue, reflecting the postnatal developmental process of the brain and cranial vault, without the need for further investigation or follow-up imaging studies.

MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review.

INTRODUCTION: MEF2C haploinsufficiency syndrome is characterized by severe intellectual disability, epilepsy, stereotypic movements, minor dysmorphisms and brain abnormalities. We report the case of a patient with a new MEF2C mutation, comparing his clinical and imaging features to those previously reported in the literature. CASE REPORT: A 10 year-old boy first came to pediatric neurology clinic at the age of 11 months because of severe psychomotor delay, without regression. He presented generalized hypotonia, poor eye contact, hand-mouth stereotypies, strabismus and minor facial dimorphisms. Epileptic seizures started at 26 months of age and were refractory. Brain MRI showed a slight increase in periventricular white matter signal and globally enlarged CSF spaces. Molecular analysis revealed a de novo, pathogenic and causative MEF2C mutation. DISCUSSION: MEF2C haploinsufficiency syndrome was recently recognized as a neurodevelopmental disorder. Severe intellectual disability with inability to speak and epilepsy are universal features in patients with MEF2C mutations, although mild cognitive and speech disorders have been reported to occur in patients with duplications. Epilepsy might be absent in patients with partial deletions. Abnormal movement patterns are very common in patients with MEF2C haploinsufficiency. Delayed myelination seems to be more commonly observed in patients with MEF2C mutations, while malformations of cortical development were only reported in patients with microdeletions. Although MEF2C haploinsufficiency prevalence is yet to be determined, it should be considered in the differential diagnosis of patients with severe intellectual disability and Rett-like features.