Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures.

TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. The TIAM1 reference (Ref) cDNA partially rescues the sif loss-of-function (LoF) phenotypes. We also assessed the function associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 Ref cDNA function in vivo. TIAM1 p.Arg23Cys has reduced rescue ability when compared to TIAM1 Ref, suggesting that it is a partial LoF variant. In ectopic expression studies, both wild-type sif and TIAM1 Ref are toxic, whereas the three variants (p.Leu862Phe, p.Arg23Cys, and p.Gly328Val) show reduced toxicity, suggesting that they are partial LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy.

Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures. Three siblings were found homozygous for a NCDN missense variant, whereas another three unrelated individuals carried different de novo missense variants in NCDN. We assayed the missense variants for their capability to rescue impaired neurite formation in human neuroblastoma (SH-SY5Y) cells depleted of NCDN. Overexpression of wild-type NCDN rescued the neurite-phenotype in contrast to expression of NCDN containing the variants of affected individuals. Two missense variants, associated with severe neurodevelopmental features and epilepsy, were unable to restore mGluR5-induced ERK phosphorylation. Electrophysiological analysis of SH-SY5Y cells depleted of NCDN exhibited altered membrane potential and impaired action potentials at repolarization, suggesting NCDN to be required for normal biophysical properties. Using available transcriptome data from human fetal cortex, we show that NCDN is highly expressed in maturing excitatory neurons. In combination, our data provide evidence that bi-allelic and de novo variants in NCDN cause a clinically variable form of neurodevelopmental delay and epilepsy, highlighting a critical role for NCDN in human brain development.

A case report of a patient with neurodevelopmental disorder with impaired speech and hyperkinetic movements: A biallelic variant in the ZNF142 gene.

Biallelic pathogenic variations in the zinc finger protein 142 (ZNF142) gene are associated with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM). This disorder is characterized by developmental delay, intellectual disability, speech delay, and movement disorders such as dystonia, tremor, ataxia, and chorea. Here, we report a patient who exhibited common neurological features and rarely reported brain MRI findings. Exome sequencing identified a novel biallelic variant in ZNF142 (c.3528_3529delTG; p.C1176fs*5 (NM_001105537.4)). NEDISHM was first described by Khan et al. (2019) and has been reported in 39 patients to date. Furthermore, upon reviewing our in-house data covering 750 individuals, we identified three different pathogenic ZNF142 variants. It appears that the frequency of ZNF142 alleles is not as low as initially thought, suggesting that this gene should be included in new generation sequencing panels for similar clinical scenarios. Our goal is to compile and expand upon the clinical features observed in NEDISHM, providing novel insights and presenting a new variant to the literature. We also aim to demonstrate that ZNF142 pathogenic variants should be considered in neurodevelopmental diseases.

De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay.

The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype.

The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15.

In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

Auditory brainstem response findings in autism spectrum disorder speech delay population.

OBJECTIVES: Evaluate pediatric auditory brainstem response (ABR) findings in children with Autism Spectrum Disorder (ASD) after the 2013 DSM-5 update. STUDY DESIGN: This was an IRB-approved, six-year retrospective chart review evaluating ABR results from pediatric patients with speech delay. Diagnosis of ASD and other neurodevelopmental abnormalities were collected for patient stratification. METHODS: From 2017 to 2023, 148 pediatric patients with speech delay were identified through diagnosis of speech delay and underwent ABR testing. Patients were then separated into two groups: Neurotypical (N = 79) and ASD (N = 69). ABR results were obtained through chart review and waveform and interpeak latency (IPL) results were recorded. Differences in waveform and IPL results were determined via Pearson's chi-square test, with multivariate analysis accounting for race, sex, and age. RESULTS: 28 patients with ASD (40.6 %) had at least one waveform/IPL prolongation. Analysis showed an increased incidence of waveform III (p = 0.028) and IPL III-V (p = 0.03) prolongation in the ASD group compared to their neurotypical counterparts. Waveform III prolongation was noted more in females with ASD (p = 0.001) than in males. No statistically significant difference when comparing race and age was found, except in the 2-3 age range (p = 0.003). CONCLUSIONS: There were higher percentages of prolongation for all waveforms and IPLs in the ASD group versus neurotypical, though not as high as previously reported. Race and age did not appear to be factors in ABR findings though more data is needed to make clinical associations.

Case Report of Suspected Gonadal Mosaicism in FOXP1-Related Neurodevelopmental Disorder.

Heterozygous mutations in the FOXP1 gene (OMIM#605515) are responsible for a well-characterized neurodevelopmental syndrome known as "intellectual developmental disorder with language impairment with or without autistic features" (OMIM#613670) or FOXP1 syndrome for short. The main features of the condition are global developmental delay/intellectual disability; speech impairment in all individuals, regardless of their level of cognitive abilities; behavioral abnormalities; congenital anomalies, including subtle dysmorphic features; and strabismus, brain, cardiac, and urogenital abnormalities. Here, we present two siblings with a de novo heterozygous FOXP1 variant, namely, a four-year-old boy and 14-month-old girl. Both children have significantly delayed early psychomotor development, hypotonia, and very similar, slightly dysmorphic facial features. A lack of expressive speech was the leading symptom in the case of the four-year-old boy. We performed whole-exome sequencing on the male patient, which identified a pathogenic heterozygous c.1541G>A (p.Arg514His) FOXP1 mutation. His sister's targeted mutation analysis also showed the same heterozygous FOXP1 variant. Segregation analysis revealed the de novo origin of the mutation, suggesting the presence of parental gonadal mosaicism. To the best of our knowledge, this is the first report of gonadal mosaicism in FOXP1-related neurodevelopmental disorders in the medical literature.

[Application of narrow-band optical radiation with a wavelength of 650 nm in complex treatment of children with developmental speech delay]. / Primenenie uzkopolosnogo opticheskogo izlucheniya s dlinoi volny 650 nm v kompleksnom lechenii detei s zaderzhkoi rechevogo razvitiya.

OBJECTIVE: To substantiate the use of photochromotherapy (narrow-band optical radiation with an average wavelength of 650 nm) in the complex treatment of children with developmental speech delay on the type of general speech underdevelopment (GSU) of I and II degree. MATERIAL AND METHODS: A number of children equal 70 aged from 4 to 6 years with developmental speech delay were examined. All patients were randomized into 2 clinically comparable groups: the 1st (study) group included 35 patients who received medical treatment in accordance with clinical recommendations in combination with the use of narrow-band optical radiation with an average wavelength of 650nm for 10 days; the 2nd (comparison) group consisted of 35 subjects who received standard drug therapy according to the established clinical recommendations. All patients underwent a comprehensive clinical examination and a special neurological investigation, including electroencephalography and electromyography, as well as an assessment of the development of speech functions and dynamic coordination of gesture, the level of social and communication skills development and neuropsychological processes. RESULTS: The following data were obtained during the complex treatment with the inclusion of narrow-band optical radiation with an average wavelength of 650 nm (red radiation): statistically significant improvement of speech development (p<0.05); improvement of values of social adaptation skills of medium (71%) (Z=2.769; p=006) and low level (29%) (Z=2.691; p=0.007); significant positive dynamics of speech status (Z=3.911; p=0.000); spontaneous activity relief at rest, indicating normalization of muscle tone. CONCLUSION: The inclusion of photochromotherapy in standard therapeutic regimens for children with developmental speech delay on the GSU type of I, II degrees contributes to a significantly confirmed pronounced clinical improvement and can be recommended for practical health care.

Early Diagnostic Signs and the Natural History of Typical Findings in Cohen Syndrome.

OBJECTIVE: To describe the clinical presentation and long-term clinical features of a molecularly confirmed cohort with Cohen syndrome. STUDY DESIGN: Twelve patients with Cohen syndrome aged 0.2-13.9 years from 8 families with a median follow-up of 7 years were enrolled to the study. Genetic analyses were made by VPS13B and whole-exome sequencing analyses. RESULTS: Biallelic VPS13B variants, including 3 nonsense, 1 frameshift, and 1 splice-site variant, and a multiexon deletion were detected. Prader-Willi syndrome-like features such as hypotonia, small hands, round face with full cheeks, almond-shaped eyes, and micrognathia were observed in all infantile patients. Beginning from age 4 years, it was noticed that the face gradually elongated and became oval. The typical facial features of Cohen syndrome such as a long face, beak-shaped nose, and open-mouth appearance with prominent upper central incisors became evident at age 9. Other Cohen syndrome features including retinopathy (11/11), neutropenia (11/12), truncal obesity (5/12), and myopia (5/11) were detected at the median ages of 7.8, 7, 7.5, and 5 years, respectively. Eleven patients aged older than 5 years at their last examination had severe speech delay. CONCLUSIONS: A differential diagnosis of Cohen syndrome in the infancy should be made with Prader-Willi syndrome, and that the typical facial features for Cohen syndrome is prominent at age 9 years, when retinopathy, neutropenia, and truncal obesity become evident. Moreover, adding the severe speech delay to the diagnostic criteria should be considered.

An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant.

Ethylmalonic encephalopathy (EE) is a rare, severe, autosomal recessive condition caused by pathogenic variants in ETHE1 leading to progressive encephalopathy, hypotonia evolving to dystonia, petechiae, orthostatic acrocyanosis, diarrhea, and elevated ethylmalonic acid in urine. In this case report, we describe a patient with only mild speech and gross motor delays, subtle biochemical abnormalities, and normal brain imaging found to be homozygous for a pathogenic ETHE1 variant (c.586G>A) via whole exome sequencing. This case highlights the clinical heterogeneity of ETHE1 mutations and the utility of whole-exome sequencing in diagnosing mild cases of EE.

SOX5: Lamb-Shaffer syndrome-A case series further expanding the phenotypic spectrum.

To delineate further the clinical phenotype of Lamb-Shaffer Syndrome (LSS) 16 unpublished patients with heterozygous variation in SOX5 were identified either through the UK Decipher database or the study team was contacted by clinicians directly. Clinical phenotyping tables were completed for each patient by their responsible clinical geneticist. Photos and clinical features were compared to assess key phenotypes and genotype-phenotype correlation. We report 16 SOX5 variants all of which meet American College of Medical Genetics/Association for Clinical Genomic Science ACMG/ACGS criteria class IV or V. 7/16 have intragenic deletions of SOX5 and 9/16 have single nucleotide variants (including both truncating and missense variants). The cohort includes two sets of monozygotic twins and parental gonadal mosaicism is noted in one family. This cohort of 16 patients is compared with the 71 previously reported cases and corroborates previous phenotypic findings. As expected, the most common findings include global developmental delay with prominent speech delay, mild to moderate intellectual disability, behavioral abnormalities and sometimes subtle characteristic facial features. We expand in more detail on the behavioral phenotype and observe that there is a greater tendency toward lower growth parameters and microcephaly in patients with single nucleotide variants. This cohort provides further evidence of gonadal mosaicism in SOX5 variants; this should be considered when providing genetic counseling for couples with one affected child and an apparently de novo variant.

A novel CHD3 variant in a patient with central precocious puberty: Expanded phenotype of Snijders Blok-Campeau syndrome?

Snijders Blok-Campeau syndrome is an autosomal dominant genetic disorder first described in 2018, mostly associated with de novo variants in the CHD3 gene that affects chromatin remodeling. This syndrome is characterized by developmental delay, speech delay, and intellectual disability, but only about 60 affected individuals have been reported to date. We report a de novo likely pathogenic CHD3 variant (c.5609G > A; p. (Arg1870Gln)) in a young female presenting with features of Snijders Blok-Campeau syndrome including speech delay, autism spectrum disorder, learning difficulties, characteristic facial dysmorphisms, and a feature not previously described in this syndrome, idiopathic central precocious puberty. Her puberty was controlled with monthly injections of a GnRH analogue. Targeted exome sequencing was negative for genes known to be responsible for central precocious puberty. Our case raises the possibility that variants in CHD3 gene may also result in central precocious puberty. Strengthening this association could expand the phenotypic spectrum of the Snijders Blok-Campeau syndrome and should be included in multigene panels for precocious puberty.

Speech and Language outcomes in Auditory Neuropathy Spectrum Disorder (ANSD) children managed with amplification.

OBJECTIVE: To evaluate speech and language outcomes in children with Auditory Neuropathy Spectrum Disorder (ANSD) without significant comorbidities who received hearing rehabilitation in the form of hearing aids and/or cochlear implantation. METHODS: Retrospective chart review of pediatric ANSD patients at a large academic tertiary care institution from 2010 to 2019. Patients were included if they received a diagnosis of bilateral ANSD, had minimal to no comorbidities, and had speech and language testing (SLT) on at least two occasions. RESULTS: 51 patients were reviewed and 7 met inclusion criteria. Average age at ANSD diagnosis was 1 year and 11 months, and average age of hearing aid fitting was 3 years and 3 months. Hearing loss ranged from mild to profound, with four of the children wearing behind (BTE) hearing aids and three eventually receiving cochlear implants. Four of five patients who received hearing aids prior to their first speech and language evaluation demonstrated a delay at their initial evaluation, and all five patients continued to demonstrate a delay at their most recent evaluation, despite appropriate audiologic management and speech and language therapy. There were two patients who were unaided at the time of their initial and latest evaluations; one patient showed a delay at both timepoints, and one patient showed no speech delay at either timepoint. CONCLUSIONS: Pediatric ANSD patients, who are otherwise typically developing and received hearing rehabilitation and speech and language therapy, continue to show a speech and language delay (SLD). This outcome underscores the importance of close monitoring of speech and language development, providing early amplification and/or cochlear implantation, and promoting additional education and psychosocial support.

Detection of copy number variants and genes by chromosomal microarray in an Emirati neurodevelopmental disorders cohort.

Copy number variations (CNVs) are highly implicated in the etiology of neurodevelopmental disorders (NDDs), and chromosomal microarray analysis (CMA) has been recommended as a first-tier test for many NDDs. We undertook a study to identify clinically relevant CNVs and genes in an ethnically homogenous population of the United Arab Emirates. We genotyped 98 patients with NDDs using genome-wide chromosomal microarray analysis, and observed 47.1% deletion and 52.9% duplication CNVs, of which 11.8% are pathogenic, 23.5% are likely pathogenic, and 64.7% VOUS. The average size of copy number losses (3.9 Mb) was generally higher than of gains (738.4 kb). Analysis of VOUS CNVs for constrained genes (enrichment for brain critical exons and high pLI genes) yielded 7 unique genes. Among these 7 constrained genes, we propose FNTA and PXK as potential candidate genes for neurodevelopmental disorders, which warrants further investigation. Thirty-two overlapping CNVs (Decipher and ClinVar) containing the FNTA gene were previously identified in NDD patients and 6 overlapping CNVs (Decipher and ClinVar) containing the PXK gene were previously identified in NDD patients. Our study supports the utility of CMA for CNV profiling which aids in precise genetic diagnosis and its integration into therapeutics and management of NDD patients.

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction.

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.

A multinational study of acute and long-term outcomes of Type 1 galactosemia patients who carry the S135L (c.404C > T) variant of GALT.

Patients with galactosemia who carry the S135L (c.404C > T) variant of galactose-1-P uridylyltransferase (GALT), documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L.

Screen time of children with speech delay: a cross-sectional study in a tertiary center in Kuantan, Malaysia.

BACKGROUND: Studies suggest excessive screen time (use of smartphones, televisions, computers and/or video games) is linked to speech and language delay. This study explored the sociodemographic characteristics of children with speech delay in Kuantan, Malaysia, and the association of screen time with speech and other developmental delays. METHODS: This cross-sectional study was conducted between July and November 2019 at the child psychiatry and speech therapy clinics, at Kuantan Hospital, Pahang, Malaysia. Parents of children with speech delay aged <72 months provided information on their children's and their own screen times. Speech and other developmental skills were assessed using the Schedule of Growing Skills II with scores reported as developmental quotient (DQ) level. RESULTS: The study included 91 children (67 boys, 24 girls) of whom 54.9% had primary speech delay and 45.1% had neurodevelopmental disorders; their mean age was 39.9 ± 11.52 months. The children's mean screen time was 2.26 ± 1.98 h daily, with 36.3% exceeding 2 h. Higher children's screen time was moderately correlated with higher parental screen time (rs = 0.479, P < 0.01). Household income was positively correlated with screen times of the children and the parents (rs = 0.243, P = 0.02 and rs = 0.390, p < 0.01, respectively). Parents who intended to reduce their children's screen time reported higher screen time in their children (t(89) = 2.322, P = 0.023). Children's age was positively correlated with the number of types of screen media (rs = 0.225, P = 0.032). The mean speech DQ was 54.76 ± 24.06%. Lower speech DQ was associated with lower DQs in other skills (P < 0.01). No significant correlation was shown between children's and parents' screen time with DQs of speech and other skills (P > 0.05). CONCLUSION: The correlation between parent and child screen time provides an opportunity for possible intervention, where necessary. Larger studies are required to examine this correlation further.