Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the
gene causing GDACCF syndrome (global ...developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far.
As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals.
The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the
gene. Heterozygous deletion including the entire
gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families.
The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with '
-related neurodevelopmental disorder'.
The field of dysmorphology has been changed by the use Artificial Intelligence (AI) and the development of Next Generation Phenotyping (NGP). The aim of this study was to propose a new NGP model for ...predicting KS (Kabuki Syndrome) on 2D facial photographs and distinguish KS1 (KS type 1, KMT2D-related) from KS2 (KS type 2, KDM6A-related). We included retrospectively and prospectively, from 1998 to 2023, all frontal and lateral pictures of patients with a molecular confirmation of KS. After automatic preprocessing, we extracted geometric and textural features. After incorporation of age, gender, and ethnicity, we used XGboost (eXtreme Gradient Boosting), a supervised machine learning classifier. The model was tested on an independent validation set. Finally, we compared the performances of our model with DeepGestalt (Face2Gene). The study included 1448 frontal and lateral facial photographs from 6 centers, corresponding to 634 patients (527 controls, 107 KS); 82 (78%) of KS patients had a variation in the KMT2D gene (KS1) and 23 (22%) in the KDM6A gene (KS2). We were able to distinguish KS from controls in the independent validation group with an accuracy of 95.8% (78.9-99.9%, p < 0.001) and distinguish KS1 from KS2 with an empirical Area Under the Curve (AUC) of 0.805 (0.729-0.880, p < 0.001). We report an automatic detection model for KS with high performances (AUC 0.993 and accuracy 95.8%). We were able to distinguish patients with KS1 from KS2, with an AUC of 0.805. These results outperform the current commercial AI-based solutions and expert clinicians.
Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with ...early‐onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage‐dependent potassium channel Kv2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv2.1. We also report the first inherited variant (p.Arg583*). KCNB1‐related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty‐five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C‐terminal domain are associated with a less‐severe epileptic phenotype. Overall, this report provides an up‐to‐date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.
KCNB1 encodes the α subunit of the delayed rectifier voltage‐dependent potassium channel Kv2.1. In this mutation update, we provide an up‐to‐date review of the mutational and clinical spectrum of the KCNB1 encephalopathy and report 18 novel variants.
Many studies have suggested that prenatal and perinatal factors increase the risk for autism spectrum disorder (ASD). However, few reports have addressed the question of their influence on the ...severity of the clinical presentation of children with ASD. Our objective was to determine the prenatal and perinatal factors that are associated with the severity of autistic symptoms and intellectual and adaptive functioning deficits. Data were collected from a subset of 169 children with a confirmed diagnosis of ASD, recruited from the ELENA cohort. A risk of premature delivery was associated, with an increased risk for severe autistic symptoms and placental pathologies and birth complications were associated with an increased risk of communication adaptive deficits, in multivariate analysis. Our results highlight the importance of systematic screening for these pre/perinatal factors, especially in mothers at risk of having a child with ASD.
•Risk of premature delivery associated with a risk of severe autistic symptoms.•Placental pathologies associated with a risk of communication adaptative deficits.•Birth complications associated with a risk of communication adaptative deficits.
Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured ...by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age‐ and sex‐matched mean (−2SD) at birth and −3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle‐like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster “abnormal spindle” gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss‐of‐function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM‐related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.
Loss‐of‐function mutations in the Abnormal SPindle‐like Microcephaly gene (ASPM) cause MicroCephaly Primary Hereditary (MCPH) type 5, defined by reduced brain volumes associated with intellectual disability. We compiled the molecular, clinical, neuroradiological and neuropsychological features of 47 patients (39 families, 28 novel mutations), and reviewed those of 282 previously reported families. We report that ASPM‐related microcephaly is not systematically associated with intellectual deficiency and discuss the association between structural brain defects (strongly reduced cortical volume and surface area) and cognitive abilities.
ABSTRACT
Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual ...disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up‐to‐date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well‐defined X‐linked KS type 2, and comment on phenotype–genotype correlations as well as sex‐specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki‐like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.
Kabuki syndrome is a rare genetic condition that is caused by mutations in the KMT2D gene in approximately 56%–75% of cases and by mutations in KDM6A in 5%–8%. We present a mutation screening of 347 patients with Kabuki syndrome, which identified 208 mutations in KMT2D, as well as twelve novel KDM6A mutations. We discuss the molecular and clinical findings in this large cohort and compare them to the literature with a focus on the rarer X‐linked Kabuki syndrome type 2.
Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few ...syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C.
Summary
Objective
IQSEC2 is an X‐linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic ...variants.
Methods
Forty‐eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians.
Results
Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male‐to‐female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic–clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late‐onset epileptic spasms (three) and Lennox‐Gastaut or Lennox‐Gastaut–like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features.
Significance
The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.
Smith‐Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point ...mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night‐time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.
Smith‐Magenis Syndrome (SMS) is a rare disease due to either a small loss in the chromosome 17 or a mutation in a specific gene at the same location. This neurodevelopmental disorder is characterized by learning and intellectual disabilities, behavioral disorder and a specific sleep disturbance with an inversion of the day‐night cycle. Here, we report an important number of SMS patients and thus provide a better support for patients and families.
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