scholarly journals Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2617-2630 ◽  
Author(s):  
Diana Le Duc ◽  
Cecilia Giulivi ◽  
Susan M Hiatt ◽  
Eleonora Napoli ◽  
Alexios Panoutsopoulos ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Wnt Pathway ◽  
De Novo ◽  
Autism Spectrum ◽  
Neural Progenitors ◽  
Scaffolding Protein ◽  
Published Data ◽  
Ph Domain ◽  
Human Phenotype ◽  
Neurodevelopmental Delay

Abstract The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.

IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

2021 ◽  
Author(s):  
Evan Jiang ◽  
Mark P. Fitzgerald ◽  
Katherine L. Helbig ◽  
Ethan M. Goldberg
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Synapse Formation ◽  
De Novo ◽  
Interleukin 1 ◽  
Autism Spectrum ◽  
Neurological Dysfunction ◽  
Behavioral Disorder ◽  
Clinical Genetic ◽  
Severe Intellectual Disability

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

scholarly journals Identification of an Identical de Novo SCAMP5 Missense Variant in Four Unrelated Patients With Seizures and Severe Neurodevelopmental Delay

2020 ◽  
Vol 11 ◽  
Author(s):  
Xianru Jiao ◽  
Manuela Morleo ◽  
Vincenzo Nigro ◽  
Annalaura Torella ◽  
Stefano D’Arrigo ◽  
...  
Keyword(s):  
Language Development ◽  
Developmental Disorders ◽  
De Novo ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Autism Spectrum ◽  
Neurodevelopmental Delay ◽  
Dysmorphic Features ◽  
Severe Intellectual Disability ◽  
Neurological Exam

Objective: To establish and broaden the phenotypic spectrum of secretory carrier membrane protein (SCAMP5) associated with epilepsy and neurodevelopmental delay.Methods: A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. SCAMP5 pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Result: The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic SCAMP5 de novo variant (p. Gly180Trp).Conclusion: Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous SCAMP5 variant might have a regressive course; language development was more severely affected.

scholarly journals Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Teresa M. Kohlenberg ◽  
M. Pilar Trelles ◽  
Brittany McLarney ◽  
Catalina Betancur ◽  
Audrey Thurm ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Intellectual Disability ◽  
Psychiatric Disorders ◽  
Psychiatric Illness ◽  
Psychiatric Symptoms ◽  
Structured Interview ◽  
Autism Spectrum ◽  
Scaffolding Protein ◽  
International Registry ◽  
Increased Risk

Abstract Background Phelan-McDermid syndrome (PMS) is a genetic condition characterized by intellectual disability, speech and language deficits, hypotonia, autism spectrum disorder, and epilepsy. PMS is caused by 22q13.33 deletions or mutations affecting SHANK3, which codes for a critical scaffolding protein in excitatory synapses. SHANK3 variants are also known to be associated with an increased risk for regression, as well as for psychiatric disorders, including bipolar disorder and catatonia. This study aimed to further describe these phenomena in PMS and to explore any relationship between psychiatric illness and regression after early childhood. Methods Thirty-eight people with PMS were recruited to this study through the Phelan-McDermid Syndrome Foundation based on caregiver report of distinct development of psychiatric symptoms. Caregivers completed a clinician-administered semi-structured interview focused on eliciting psychiatric symptomatology. Data from the PMS International Registry were used to confirm genetic diagnoses of participants and to provide a larger sample for comparison. Results The mean age of the 38 participants was 24.7 years (range = 13 to 50; SD = 10.06). Females (31 of 38 cases; 82%) and sequence variants (15 of 38 cases; 39%) were over-represented in this sample, compared to base rates in the PMS International Registry. Onset of psychiatric symptoms occurred at a mean age of 15.4 years (range = 7 to 32), with presentations marked by prominent disturbances of mood. Enduring substantial loss of functional skills after onset of psychiatric changes was seen in 25 cases (66%). Symptomst indicative of catatonia occurred in 20 cases (53%). Triggers included infections, changes in hormonal status, and stressful life events. Conclusions This study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in adolescence or early adulthood, including bipolar disorder, catatonia, and lasting regression of skills. These findings should increase the awareness of these phenotypes and lead to earlier diagnosis and the implementation of appropriate interventions. Our findings also highlight the importance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric disorders and regression among larger unbiased samples of individuals with PMS.

scholarly journals A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability

2015 ◽  
Vol 24 (6) ◽  
pp. 838-843 ◽  
Author(s):  
Anne-Laure Mosca-Boidron ◽  
Lucie Gueneau ◽  
Guillaume Huguet ◽  
Alice Goldenberg ◽  
Céline Henry ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals KBG Syndrome: Prospective Videoconferencing and Use of AI-driven Facial Phenotyping in 25 New Patients

2021 ◽  
Author(s):  
Lily Guo ◽  
Jiyeon Park ◽  
Edward Yi ◽  
Elaine Marchi ◽  
Yana Kibalnyk ◽  
...  
Keyword(s):  
De Novo ◽  
Autism Spectrum ◽  
Nasal Bridge ◽  
Human Phenotype ◽  
Behavioral Issues ◽  
Eeg Abnormalities ◽  
Repeat Domain ◽  
Gastrointestinal Complaints ◽  
Kbg Syndrome ◽  
Recurrent Sinus

Genetic variants in the gene Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families, all with molecularly confirmed diagnoses of KBG syndrome. Twenty-one individuals have de novo variants, three have inherited variants, and one is inherited from a mother exhibiting low-level mosaicism. Of these variants, 20 are truncating (frameshift or nonsense), and five are missense. We created a novel protocol for collection and reporting of data, including prospectively interviewing these individuals and their families throughout eight countries via videoconferencing by a single clinician. Participants' medical records, including imaging, were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were submitted to GestaltMatcher and Face2Gene (FDNA Inc, USA) for facial analysis, and we found similar facial phenotypes among the participants. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Seventy-two percent of participants had gastrointestinal complaints and 80% had hearing loss. Three participants were started on growth hormone with positive results. Behavioral issues and global developmental delays were found in most participants. Neurologic abnormalities including seizures and/or EEG abnormalities were also very common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Twenty-four percent were diagnosed with attention deficit hyperactivity disorder (ADHD) and 28% were diagnosed with autism spectrum disorder (ASD). Additionally, we have identified minimally reported symptoms, including recurrent sinus infections (16%) and previously unreported migraines (20%). Based on the videoconferencing and these data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

scholarly journals De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences

2019 ◽  
Vol 4 (3) ◽  
pp. 476-481 ◽  
Author(s):  
Takuya Hiraide ◽  
Ayako Hattori ◽  
Daisuke Ieda ◽  
Ikumi Hori ◽  
Shinji Saitoh ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals A 9-year-old-girl with Phelan McDermid Syndrome, who had been diagnosed with an autism spectrum disorder

2016 ◽  
Vol 19 (2) ◽  
pp. 85-90 ◽  
Author(s):  
I Görker ◽  
H Gürkan ◽  
S Demir Ulusal ◽  
E Atlı ◽  
E Ikbal Atlı
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Comparative Genomic ◽  
Parental Origin ◽  
Mild Intellectual Disability ◽  
First Case

AbstractPhelan McDermid Syndrome (PHMDS) (OMIM #606232), is a contiguous gene disorder resulting from deletion of the distal long arm of chromosome 22. The 22q13.3 deletions and mutations that lead to a loss of a functional copy of SHANK3 (OMIM *606230) cause the syndrome, characterized by moderate to profound intellectual disability, severely delayed or absent speech, hypotonia, and autism spectrum disorder (ASD) or ASD traits. In this study, we present the case of a 9-year-old girl who had earlier been diagnosed with an ASD. Our findings were a clinically mild intellectual disability, rounded face, pointed chin but no autistic findings. We learned that her neuromotor development was delayed and she had neonatal hypotonia in her history. A heterozygous deletion of MLC1, SBF1, MAPK8IP2, ARSA, SHANK3 and ACR genes, located on 22q13.33, was defined by multiplex ligation-dependent probe amplification (MLPA). Deletion of 22q13.3 (ARSA) region was confirmed by a fluorescent in situ hybridization (FISH) technique. The 22q13.3 deletion was found to be de novo in our patient, and she was diagnosed with PHMDS. We confirmed the 22q13.3 deletion and also determined a gain of 8p23.3-23.2 by array comparative genomic hybridization (aCGH). Fluorescent in situ hybridization was performed to determine whether the deletion was of parental origin and to identify regions of chromosomes where the extra 8p may have been located. The parents were found to be normal. The extra copy of 8p was observed on 22q in the patient. She is the first case reported in association with the 22q deletion of 8p duplications in the literature.

scholarly journals A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder

2018 ◽  
Vol 26 (9) ◽  
pp. 1388-1391 ◽  
Author(s):  
Maria Barington ◽  
Lotte Risom ◽  
Jakob Ek ◽  
Peter Uldall ◽  
Elsebet Ostergaard
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
De Novo ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals First Report of a de novo 10q23.31q23.33 Microdeletion: Obesity, Intellectual Disability and Microcephaly

2021 ◽  
pp. 1-5
Author(s):  
Ayberk Turkyilmaz ◽  
Erdal Kurnaz ◽  
Atilla Cayir
Keyword(s):  
Intellectual Disability ◽  
Array Cgh ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Autism Spectrum ◽  
Comparative Genomic ◽  
Facial Dysmorphism ◽  
Genetic And Environmental Factors

Intellectual disability (ID) is characterized by limited or insufficient development of mental abilities, including intellectual functioning impairments, such as learning and understanding cause-effect relationships. Some cases have ID as the only finding and are called isolated cases. Conversely, cases accompanied by facial dysmorphism, microcephaly, autism spectrum disorder, epilepsy, obesity, and congenital anomalies are called syndromic developmental delay (DD)/ID. Isolated and syndromic DD/ID cases show extreme genetic heterogeneity. Genetic etiology can be detected in approximately 40% of the cases, whereas chromosomal abnormalities are observed in 25%. Obesity is a multifactorial disease in which both genetic and environmental factors play important roles. The role of heredity in obesity has been reported to be between 40 and 70%. Array-based comparative genomic hybridization (array-CGH) can detect CNVs in the whole genome at a higher resolution than conventional cytogenetic methods. Array-CGH is currently recommended as the first-tier genetic test for ID cases worldwide. In the present study, we aimed to evaluate clinical, radiological, and genetic analyses of a 12-year and 4-month-old girl with microcephaly, ID, and obesity. In the array-CGH analysis, a 3.1-Mb deletion, arr[GRGh37] 10q23.31g23.33 (92745793_95937944)×1 was detected, and this alteration was evaluated to be pathogenic. We consider that haploinsufficiency of the candidate genes (<i>GPR120</i>, <i>KIF11</i>, <i>EXOC6</i>, <i>CYP26A1</i>, <i>CYP26C1</i>, and <i>LGI1</i>) in the deletion region may explain microcephaly, ID, obesity, seizures, and ophthalmological findings in our patient. The investigation of 10q23.31q23.33 microdeletion in cases with syndromic obesity may contribute to molecular genetic diagnosis.

scholarly journals Case Report: Bilateral Epiphysiodesis Due to Extreme Tall Stature in a Girl With a De Novo DNMT3A Variant Associated With Tatton-Brown-Rahman Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Otto Lennartsson ◽  
Maria Lodefalk ◽  
Henrik Wehtje ◽  
Eva-Lena Stattin ◽  
Lars Sävendahl ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Clinical Case ◽  
Distal Femur ◽  
De Novo ◽  
Bone Age ◽  
Autism Spectrum ◽  
Tall Stature ◽  
Leg Length ◽  
Early Puberty

ObjectiveTo present a rare clinical case of a patient with Tatton-Brown-Rahman syndrome and the outcome of tall stature management with bilateral epiphysiodesis surgery at the distal femur and proximal ends of tibia and fibula.Study DesignClinical case report.ResultsThis is a 20-year-old female with a history of proportional tall stature, developmental psychomotor and language delay with autism spectrum behavior and distinctive facial features. At 12 years and 2 months of age she was in early puberty and 172.5 cm tall (+ 2.8 SDS) and growing approximately 2 SDS above midparental target height of 173 cm (+ 0.9 SDS). A bone age assessment predicted an adult height of 187.1 cm (+3.4 SDS). To prevent extreme tall stature, bilateral epiphysiodesis surgery was performed at the distal femur and proximal ends of tibia and fibula at the age of 12 years and 9 months. After the surgery her height increased by 12.6 cm to 187.4 cm of which approximately 10.9 cm occurred in the spine whereas leg length increased by only 1.7 cm resulting in a modest increase of sitting height index from 50% (-1 SDS) to 53% (+ 0.5 SDS). Genetic evaluation for tall stature and intellectual disability identified a de novo nonsense variant in the DNMT3A gene previously associated with Tatton-Brown-Rahman syndrome.ConclusionTatton-Brown-Rahman syndrome should be considered in children with extreme tall stature and intellectual disability. Percutaneous epiphysiodesis surgery to mitigate extreme tall stature may be considered.

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