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ASH1L mutation caused seizures and intellectual disability in twin sisters
This paper presents twin sisters exhibiting mild intellectual disability and seizures. Whole exome sequencing of the family revealed a novel de novo heterozygous sequence variant, NM_018489.2: c.2678dup (p.Lys894*) in exon 3 of ASH1L which was estimated to be pathogenic. Loss-of-function (LOF) of ASH1L can affect the catalyzation of H3K36 methylation and cause developmental disorders. In this study, the researchers identified a de novo ASH1L truncating mutation in monozygotic twin sisters presenting with mild ID and refractory epilepsy using whole-exome sequencing. The two affected individuals were monozygotic twins. They were full-term born from healthy and non-consanguineous parents.
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Twin 1 had sleep disturbances and crying through the night from four years of age, avoidance behaviors including aberrant social behavior from five years of age, ADHD and learning difficulties. Epileptic seizures characterized by unresponsiveness to voice with frequent blinking lasting for 10–20 s emerged at the age of seven and occurred three–five times per week. At eight years of age, the child presented with generalized tonic-clonic seizures (GTCS) occurring several times per month. She was diagnosed with combined generalized and focal epilepsy. Sodium valproate (30 mg/kg) and levetiracetam (23 mg/kg) treatment resulted in reduced seizure burden and improved sleep. She has mild ID (IQ score of 75) but not ASD.
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Twin 2 presented a similar epileptic phenotype, with GTCS onset at seven years of age and spike-wave discharges observed on EEG. Treatment with sodium valproate and levetiracetam successfully reduced seizure burden. She also exhibited avoidance behavior toward strangers and learning disorders, with an IQ of 75. The evaluation for autism was negative.
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As of November 2020, 59 ASH1L mutations, including 42 missense mutations, 16 truncating mutations, and one gross deletion, have been reported. Only 12 cases, including four missense and eight truncating mutations, had detailed clinical information. Of the 14 patients, 4 (28%) carried missense variants and 10 (72%) carried truncating variants. All patients with missense variants had developmental delay, three of which (75%) were considered to be severe. All four individuals (100%) had MCA, three (75%) exhibited abnormal behavior, two (50%) had a sleep disorder, and one (25%) experienced seizure. All patients with truncating variants also had developmental delay, one of which was severe (10%). Five (50%) individuals had MCA, seven (70%) had abnormal behavior, six (60%) had a sleep disorder, and four (40%) experienced seizures. The researchers evaluated all 59 cases of reported ASH1L mutations, including those without detailed clinical information. The phenotype for each patient was classified as either ASD or ID. All variants were classified as either null (including truncation, duplication, and deletion) or missense. Missense mutations are more likely to be associated with ASD, while null mutations are associated with ID.
KEYWORDS: mild intellectual disability, seizures, sleep disturbances, crying through the night, avoidance behaviors, aberrant social behavior, ADHD, Learning Difficulties, generalized tonic-clonic seizures (GTCS), generalized and focal epilepsy
ASH1L Mutation Images
Schematic diagram of ASH1L protein including five functional domains (AWS, SET, Post-SET, Bromo, BAH, PHZ) are shown. All mutations including truncating and missense mutations are labeled by sticks. Mutations with ASD and ID are colored black and blue, respectively. Source: ASH1L mutation caused seizures and intellectual disability in twin sisters
ASH1L with novel private LGD and MIS30 mutations identified in this study (Targeted sequencing identifies 91 neurodevelopmental disorder risk genes with autism and developmental disability biases) and published DN variants indicated in HGVS format. Annotated protein domains are shown (colored blocks) for the largest protein isoforms. Previously published DN variants are compared to new variants in this study. Variants above the dashed line are of unknown inheritance; variants below the line have been validated for inheritance. Domain abbreviations: NARP1, NMDA receptor-regulated protein 1; CC, coiled coil; TRP, tetratrico peptide repeat region; PHD, plant homeodomain.
Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders
Variants of ASH1L in this study
Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings
According to the National Autism Spectrum Disorder Surveillance System (NASS) (2018), Autism Spectrum Disorder (ASD) is diagnosed in 1 in 66 Canadian children and youth (ages 5–17), making it one of the most common neurodevelopmental disorders in children. The genetic heritability of autism can reach up to 90% in early twin studies, indicating a strong genetic influence on ASD.
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The participating family for this study has three boys with ASD, born to phenotypically normal, non-consanguineous parents. The mother is a -thalassemia carrier. The mother’s paternal aunt and uncle both exhibit symptoms of obsessive-compulsive disorder (OCD) and anxiety disorder (unconfirmed). The mother’s father is anemic and is strongly suspected to have high-functioning ASD. The father is an -thalassemia carrier, and the father’s nephew has Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). All of the boys were diagnosed with ASD.
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A maternal variant in ASH1L (NP_060959.2:p.Gln433Pro) was identified only in Sib-2.
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Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. All of the above detected familial variants were found to be shared by all three children, except for the variant in ASH1L that was only detected in Sib-2. Sib-2 is the most severely affected among the three children. features. Sib-2 (14 years old) has slightly coarse facies. He shows the prominent cognitive deficits and a greater severity of ASD. He has a history of dysphagia and no anemia (not a thalassemia carrier).
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It has been demonstrated that patients with two or more de novo mutations in ASD candidate genes showed more severe phenotypes. Whether this inherited ASH1L missense variant may contribute to the more severe ASD phenotype in Sib-2 needs further functional studies.
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KEYWORDS: ASD, Autism, Slightly coarse facies, Cognitive deficits, Dysphagia
Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors
This study establishes an ASD/ID mouse model (Ash1L knockout mouse model) revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.
Generation and characterization of Ash1L knockout mice - Ash1L was dispensable for mouse embryonic development. Ash1L might be critical for establishing and maintaining a stable physiological condition for neonatal survival. . Similar to the craniofacial deformity observed in patients, mice displayed an abnormal craniofacial appearance with a reduced eye-to-mouth distance.
Loss of ASH1L delays embryonic and postnatal brain development - Ash1L deletion in the developing mouse brain resulted in the delayed lamination of neuronal cells during embryonic cortical layer formation. Ash1L deletion in the developing brain led to delayed myelination during early postnatal brain development.
Loss of ASH1L in the developing mouse brain causes ASD/IDlike behaviors - The loss of Ash1L in the developing mouse brain resulted in both autistic-like behaviors and ID-like defects, which were featured by reduced sociability, loss of interest in social novelty, repetitive and compulsive behaviors, impaired recognition memory, and increased anxiety-like behaviors.
Loss of ASH1L impairs expression of genes critical for brain development - . Ash1L is highly expressed in the embryonic and adult mouse brain, suggesting its possible role in brain development and function. Multiple genes downregulated in the Ash1L-KO cells, such as Emx2, Dbx2, Pcdh10, Sall3, and Foxg1, were previously reported to be involved in normal brain development and NDDs.
Disruptive ASH1L gene mutations found in patients are likely to be the causative drivers leading to clinical ASD/ID. Ash1L might also play important roles in establishing neural circuits in the developing hypothalamus, which is critical for normal feeding behaviors and early postnatal growth. The loss of Ash1L in NPCs leads to delayed brain development in both neuronal and glial lineages. Multiple genes critical for normal brain development and highly related to human ASD/ID were found to have reduced expression in the differentiating Ash1L-KO NPCs, suggesting that impaired expression of neurodevelopmental genes is likely to be a main molecular mechanism linking ASH1L mutations to abnormal brain development. ASH1L might function as a master epigenetic regulator to facilitate the expression of FOXG1 and other critical genes for normal brain development, while mutations of ASH1L lead to mis-regulation of gene expression, disturbance of the normal brain developmental program, and brain functional abnormalities of ASD/ID.
KEYWORDS: ASD, Autism, ID, Intellectual Disability, reduced sociability, loss of interest in social novelty, repetitive and compulsive behaviors, impaired recognition memory, and increased anxiety-like behaviors, delayed myelination, delayed lamination
The Histone Methyltransferase Ash1l is Required for Epidermal Homeostasis in Mice
In this paper it is shown that mice carrying a hypomorphic mutation of the histone methyltransferase Ash1l develop epidermal hyperplasia and impaired epidermal stratification upon aging. In adult mutants, loss of Ash1l leads to more proliferative keratinocytes in disturbed differentiation stages. After wounding, Ash1l mutation leads to delayed re-epithlialization but increased keratinocyte proliferation at the wound edge. Elevated c-Myc expression could be observed in both aged and wounded mutant tissues. Taken together, these observations revealed an important role of the epigenetic regulator Ash1l in epidermal homeostasis.
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Disruption of Ash1l leads to epidermal hyperplasia in aged mice. The epidermal hyperplasia in Ash1l mutants suggested that Ash1l is required for epidermal homeostasis.
Ash1l mutation causes disturbed keratinocyte differentiation in adult mice. Ash1l mutation causes over proliferation of keratinocyte in adult mice. Ash1l PB/PB mice have wound healing defects. Loss of Ash1l hamper wound healing. ASH1L antagonizes H3K27 tri-methylation and c-Myc expression. It is likely that Ash1l stimulates c-Myc expression in epidermis by altering histone modifications.
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In this study, it has been shown that disruption of Ash1l leads to disturbed epidermal differentiation, excessive keratinocyte proliferation, defective wound healing, and skin hyperplasia in adult mice. These results suggest Ash1l as an important regulator of epidermal homeostasis.
Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures
This paper identifies ASH1L as a candidate gene for seizures.
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ASH1L (absent, small or homeotic disc 1 like histone lysine methyltransferase) encodes histone methyltransferase, which is involved in histone and chromatin modification and gene regulation. Ash1L is enriched in the brain in mice, and a role in epigenetic modification in brain functioning was implicated when in Ash1L knockout mice the activity-dependent repression of neurexin 1α, a presynaptic adhesion molecule required for synaptic formation, was completely abolished.
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The identified ASH1L patient details:
c.DNA:Protein change = c.C4024T:p.Arg1342*
De novo
Seizure phenotype = 7 y M, seizure onset at 6 mo with MA, myoclonic, GTC, absence, and tonic seizures. Seizures refractory to treatment.
EEG Report = GSW and polyspike; focal activity maximal in right temporal region
Additional Clinical Features = Moderate to severe ID, ASD, ADHD
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Seven other de novo ASH1L variants have been reported in ID/ASD patients. Only one case has been described with an epilepsy phenotype; the patient had a missense ASH1L variant of unknown inheritance, leaving its pathogenic role uncertain.
KEYWORDS: ASD, Autism, Intellectual Disability, ID, ADHD, Seizures - MA, Myoclonic, GTC, Absence, Tonic
Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability
This study has identified ASH1L as novel autosomal-dominant ID genes. It is increasingly plausible that LoF variants in ASH1L are sufficient to cause disease in the affected individuals.
De novo genic mutations among a Chinese autism spectrum disorder cohort
Recurrent de novo (DN) and likely gene-disruptive (LGD) mutations contribute significantly to autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, the researchers have sequenced 189 risk genes in 1,543 Chinese ASD probands (1,045 from trios). The most prevalent gene for recurrent DN mutations is SCN2A (1.1% of patients) followed by CHD8, DSCAM, MECP2, POGZ, WDFY3 and ASH1L.
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As per this paper, in Autism Clinical and Genetic Resources in China (ACGC), there are 3 cases of de novo ASH1L missense mutation, followed by 2 LGD in Simons Simplex Collection (SSC) and 1 LGD in Autism Sequencing Consortium (ASC).
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Patient Clinical phenotypes observed:
Protein change = p.Val2080Ile
Phenotypes = ASD, ID, Speech Delay, Repetitive behaviour, Macrocephaly, Mild Regression, Sleep problems, GI Disturbances, Hyperactive behaviour, Attention problems, anxiety, Obsessive behaviour
Targeted sequencing identifies 91 neurodevelopmental disorder risk genes with autism and developmental disability biases
For ASH1L, the researchers identified two DN LGD and two DN MIS30 mutations in addition to the three DN LGD previously published mutations13,14. They identified many additional LGD and MIS30 variants in ASH1L where parental DNA was not available and found that mutations cluster around the known annotated protein domains. They were able to obtain clinical information for two probands carrying private and three probands carrying ultra-rare ASH1L variants. Individuals with ASH1L disruptive variation in this study had ID (5/5 patients [100%]), ASD (2/3 patients [67%]), and evidence of seizures (2/3 patients [67%]).
Ash1 (ortholog of ASH1L) neuronal knockdown flies showed reduced fitness. Mouse studies have shown that Ash1l protein represses nrxn1α protein in neurons—a known presynaptic adhesion molecule required for synaptic formation; mutations in NRXN1 have been associated with ASD.
ASH1L with novel private LGD and MIS30 mutations identified in this study and published DN variants indicated in HGVS format. Annotated protein domains are shown (colored blocks) for the largest protein isoforms. Previously published DN variants are compared to new variants in this study. Variants above the dashed line are of unknown inheritance; variants below the line have been validated for inheritance. Domain abbreviations: NARP1, NMDA receptor-regulated protein 1; CC, coiled coil; TRP, tetratrico peptide repeat region; PHD, plant homeodomain.
Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders
This paper provides evidence to firmly associate ASH1L haploinsufficiency with dominant developmental disorders.
Individual 1; de novo c.3033delA; p.Val1014Cysfs*24 mutation
This is a 13-year-old female born to non-consanguineous healthy parents. She was noted to have cardiac anomalies prenatally. She had neonatal feeding difficulties. She was detected to have a bicuspid aortic valve, ventricular septal defect and a patent foramen ovale that were closed surgically. She had normal early development but mild to moderate intellectual disability was evident from primary school age. She has behavioural problems such as trichotillomania. She has hypermetropia and precocious puberty. At 12.6 years of age her height was 156.8 cm (0.2 SD) and head circumference was 55.1 cm (1.16 SD). She has a prominent chin and hypermobile small joints.
Individual 2; de novo c.7276C>T; p.Arg2426Ter mutation
This is a 9-year-old male born to non-consanguineous healthy parents. He was noted to have unilateral hydronephrosis prenatally that resolved on spontaneously. He had neonatal feeding difficulties. He had severe global developmental delay. He could sit unsupported at 9 months, walked independently from 2-2.5 years of age, and said his first words from 4-5 years of age. He has intellectual disability, seizures, autism and hypotonia. He has hyperacusis, hypermetropia, cryptorchidism and an inguinal hernia. At 8 years of age his height was 141.8 cm (1.6 SD); weight was 44.5 Kg (2.33 SD) and head circumference was 56.3 cm (1.36 SD). He has high anterior hairline, low posterior hairline, U-shaped upper lip vermilion, downturned corners of mouth, and joint hypermobility.
Individual 3; de novo 532.9 Kb deletion encompassing ASH1L
This is a 7-year-old male born to non-consanguineous healthy parents following a twin pregnancy. He has severe global developmental delay. He could sit unsupported at 11 months, walked independently from 30 months of age, and said his first words from 3 years of age. He is sociable. He has a blocked nasolacrimal duct, cryptorchidism and constipation on treatment with macrogol 3350. At 4 years of age his height was 100 cm (- 0.59 SD); weight was 15.5 Kg (-0.44 SD) and head circumference was 48.5 cm (-1.72 SD). He has brachycephaly, epicanthic folds, 5th finger clinodactyly and pes planus.
Locations of selected plausible candidate variants identified in this study are shown. Candidate genes for dominant DDs with DN PTVs are indicated in red font, and the other genes are in black font.
Rare high quality variants in KMT/KDM genes not known to be associated with developmental disorders
Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures
This paper identifies ASH1L as a candidate gene for seizures.
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ASH1L (absent, small or homeotic disc 1 like histone lysine methyltransferase) encodes histone methyltransferase, which is involved in histone and chromatin modification and gene regulation. Ash1L is enriched in the brain in mice, and a role in epigenetic modification in brain functioning was implicated when in Ash1L knockout mice the activity-dependent repression of neurexin 1α, a presynaptic adhesion molecule required for synaptic formation, was completely abolished.
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The identified ASH1L patient details:
c.DNA:Protein change = c.C4024T:p.Arg1342*
De novo
Seizure phenotype = 7 y M, seizure onset at 6 mo with MA, myoclonic, GTC, absence, and tonic seizures. Seizures refractory to treatment.
EEG Report = GSW and polyspike; focal activity maximal in right temporal region
Additional Clinical Features = Moderate to severe ID, ASD, ADHD
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Seven other de novo ASH1L variants have been reported in ID/ASD patients. Only one case has been described with an epilepsy phenotype; the patient had a missense ASH1L variant of unknown inheritance, leaving its pathogenic role uncertain.
KEYWORDS: ASD, Autism, Intellectual Disability, ID, ADHD, Seizures - MA, Myoclonic, GTC, Absence, Tonic
Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders
ASH1L potentially contributes to neurodevelopmental diseases. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome, autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Functional convergence of Ash1l generated several significant signaling pathways: chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function.
This paper reviews the literature on Ash1l, including its discovery, expression, function, regulation, implication in the nervous system, signaling pathway, mutations, and putative involvement in Tourette syndrome and other neurodevelopmental traits. Mutations in Ash1l confer susceptibility to TS, underlying the significance of this gene in the molecular mechanism underlying TS. Ash1l has been assumed to play a pathogenic role in other, more common neuropsychiatric illnesses.
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Mutations in Ash1l confer susceptibility to Tourette syndrome - The heterozygous mutations in Ash1l are strongly enriched for variants likely to increase nervous system disease risk including TS, ASD, ADHD, multiple congenital malformation (MCA)/intellectual disability (ID), and SCZ. ASH1L plays a critical role in maintaining active gene
expression but the definite role of Ash1l at cellular and molecular levels during brain neurodevelopment remains largely unknown. ASH1L mutant mice exhibit typical tics and over-grooming behaviors. Studies have shown that ASH1L is highly expressed in the central nervous system, especially in the striatum, primary motor cortex,
primary somatosensory cortex, and medio-dorsal nucleus of thalamus, matching the neuropathological brain regions in TS. It has been found that Ash1l binds to the promoter region of NRXN1 when screening for neural activity-dependent epigenetic regulatory factors, thereby inhibiting the transcriptional activity of NRXN1 and causing synapse formation disorder, which causes mental illness. Deleted fragments of NRXN1 in TS patients were significantly longer than those in the control group, suggesting that NRXN1 and Ash1l participate in the development of TS. Taken together, although there is convincing evidence that Ash1l plays a pathogenic role in TS, more research needs to be done on well-defined patient cohorts and further uncover the functional consequences of these disruptions.
Novel MCA/ID syndrome with ASH1L mutation
In this paper the researchers report a patient with a new MCA/ID syndrome who has a novel mutation in the ASH1L gene.
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Clinical Report - The 4 year old male was born after 40 weeks to healthy and nonconsanguineous Japanese parents. Bilateral cryptorchidism was noted. Global developmental delay was apparent during the first year of life. At the age of 1 year, he was hypotonic and could not rollover. Feeding improved over time, but chronic constipation continued. At 4 years, he showed axial hypotonia and could not sit or crawl. He spoke no words and showed severe ID. He showed self-injurious behaviors and abnormal laughter without reasons. Sleep disorder was noted. He showed dysmorphic features including hypertelorism, low set ears, a flat nasal bridge, a short upturned nose, a short philtrum, orofacial hypotonia with an open mouth appearance, a high arched palate, and down-turned corners of the mouth. Vision was impaired with horizontal nystagmus and strabismus. Moderate sensorineural deafness of the left ear was noted. Lumbar scoliosis was noted. Brain MRI revealed markedly delayed myelination of cerebral white matter.
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Results - A novel mutation in ASH1L (c.8356G>C: p.(Ala2786Pro)) was identified. This mutation was de novo and predicted to be pathogenic. This mutation is located in the highly conserved Bromo adjacent homology (BAH) domain of ASH1L.
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Discussion - Researchers of this paper identified a novel mutation in ASH1L in a patient with severe ID, growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities. Orofacial hypotonia with an open-mouth appearance and horizontal nystagmus was characteristic. A CT of the cervical spine revealed congenital fusion of C2 and C3. Severe scoliosis was also noted. Anomalies of the spine in this patient may have been the result of insufficient HOX gene expression in the fetal period. This patient showed markedly delayed myelination of the cerebral white matter. This indicates that ASH1L plays important roles in CNS development. This report further suggests that mutations of ASH1L are associated with neurogenetic abnormalities. ASH1L mutations may cause MCA/ID syndrome and nonsyndromic ID or autism.
KEYWORDS: MCA, Multiple Congenital Anomaly, ID, Intellectual Disability, Bilateral cryptorchidism, Global developmental delay, GDD, Hypotonia, Feeding problems, chronic constipation, Axial Hypotonia, Self-injurious behaviours, abnormal laughter, Sleep disorder, dysmorphic features, hypertelorism, low set ears, a flat nasal bridge, a short upturned nose, a short philtrum, orofacial hypotonia with an openmouth appearance, a high arched palate, and down-turned corners of the mouth, horizontal nystagmus and strabismus, sensorineural deafness, Lumbar scoliosis, delayed myelination of cerebral white matter, growth failure, microcephaly, facial dysmorphism, myelination delay, and skeletal abnormalities, Orofacial hypotonia, an open-mouth appearance
De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental disorder
In this paper, the researchers have identified a novel de novo frame-shift variant, c.2422_2423delAAinsT which predicts p.(Lys808TyrfsTer40), in ASH1L in a patient with multiple congenital anomalies (MCA), fine motor developmental delay, learning difficulties, attention deficit hyperactivity disorder, sleep apnea, and scoliosis. This frame-shift variant is expected to result in loss-of-function. The report provides further evidence to support loss-of-function alterations of ASH1L as causative for an emergent neurodevelopmental syndrome characterized by MCA, intellectual disability, and behavioral problems, and further delineates this genetic disorder.
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Clinical Report - This patient was a 9-year-old Caucasian boy. He was born at 35 weeks’ gestation, had jaundice that required phototherapy during the neonatal period, walked at 12 months and never had speech problems. He was diagnosed with fine motor developmental delays. He had surgery to correct penile torsion. At 5 years and 11 months of age, he had pressure equalizer (PE) tubes placed for recurrent otitis media. At age 7, brain MRI showed mild thickening of the corpus callosum. Neuropsychiatric testing at 7.5 years of age demonstrated extremely low performance in verbal comprehension, very low performance in fluid reasoning, average visual-spatial skills and lowaverage working memory. He was diagnosed with ADHD and learning difficulties. He also presented with frequent acting out and tantrums. At age 8, two sleep studies demonstrated obstructive sleep apnea and mild sleep fragmentation. His distinctive facial features included mild blepharophimosis and ptosis; downslanting, short palpebral fissures; narrow mouth and thin vermilion of upper lip; slightly long philtrum, low and mildly slender nasal bridge; narrow, high-arched palate; small ears; and a frontal upsweep. He also had mild pectus excavatum, scoliosis, and slightly short-appearing fingers.
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Discussion - All patients with de novo ASH1L variants exhibited intellectual disability regardless the variant type. Other common findings include behavioral problems including autistic features (10/11 patients), genital abnormalities in males including cryptorchidism and penile torsion (6/7 patients), and sleep disorder (5/6 patients). The affected individuals also had some less common medical problems including motor developmental delay, speech delay or speech absence, seizures, feeding difficulties, hypotonia, musculoskeletal abnormalities (pectus carinatum, pectus excavatum, scoliosis, and cervical spine fusion), ophthalmological abnormalities (hyperopia, astigmatism, strabismus, and nystagmus), hearing impairment, and gastrointestinal disturbances. These findings suggest that this emergent ASH1L-related neurodevelopmental disorder is characterized by intellectual disability, behavioral problems, sleep disorder, and MCA.
Variable clinical features have also been observed in affected individuals. For the four patients whose facial features were described, there was a lack of consensus facial features, suggesting that a broad spectrum of dysmorphic facial features may be associated with de novo ASH1L pathogenic variants.
KEYWORDS: multiple congenital anomalies (MCA), fine motor developmental delay, learning difficulties, attention deficit hyperactivity disorder, sleep apnea, scoliosis, intellectual disability, ID, penile torsion, pressure equalizer (PE) tubes, recurrent otitis media, mild thickening of the corpus callosum, behavioural problems, frequent acting out, tantrums, obstructive sleep apnea, mild sleep fragmentation, distinctive facial features, mild blepharophimosis, ptosis, downslanting, short palpebral fissures; narrow mouth and thin vermilion of upper lip; slightly long philtrum, low and mildly slender nasal bridge; narrow, high-arched palate; small ears; and a frontal upsweep, mild pectus excavatum, scoliosis, and slightly short-appearing fingers