Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder.

Pathogenic variants in BRPF1 cause intellectual disability, ptosis and facial dysmorphism. Speech and language deficits have been identified as a manifestation of BRPF1-related disorder but have not been systematically characterized. We provide a comprehensive delineation of speech and language abilities in BRPF1-related disorder and expand the phenotype. Speech and language, and health and medical history were assessed in 15 participants (male = 10, median age = 7 years 4 months) with 14 BRPF1 variants. Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains. Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9). All those tested for cognitive abilities had a FSIQ ≥70 (4/4). Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15). We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech. Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders. The universal involvement of speech and language impairment is noteable, relative to the high degree of phenotypic variability in BRPF1-related disorder.

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder.

Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. We did not detect significant associations between the language-related tests and language-related PRS. Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the condition.

Prenatal prevalence and postnatal manifestations of 16p11.2 deletions: A new insights into neurodevelopmental disorders based on clinical investigations combined with multi-omics analysis.

BACKGROUND: The 16p11.2 deletion is one of the most common genetic aetiologies of neurodevelopmental disorders (NDDs). The prenatal phenotype of 16p11.2 deletion and the potential mechanism associated with postnatal clinical manifestations were largely unknow. We revealed the developmental trajectories of 16p11.2 deletion from the prenatal to postnatal periods and to identify key signaling pathways and candidate genes contributing to neurodevelopmental abnormalities. METHODS: In this 5-y retrospective cohort study, women with singleton pregnancies who underwent amniocentesis for chromosomal abnormalities were included. Test of copy-number variations (CNVs) involved single nucleotide polymorphism-array and CNV-seq was performed to detected 16p11.2 deletion. For infants born carrying the 16p11.2 deletion, neurological and intellectual evaluations using the Chinese version of the Gesell Development Scale. For patients observed to have vertebral malformations, Sanger sequencing for T-C-A haplotype of TBX6 was performed. For those infants with clinical manifestations, whole-exome sequencing was consecutively performed in trios to rule out single-gene diseases, and transcriptomics combined with untargeted metabolomics were performed. RESULTS: The prevalence of 16p11.2 deletion was 0.063% (55/86,035) in the prenatal period. Up to 80% (20/25) of the 16p11.2 deletions were proven de novo by parental confirmation. Approximately half of 16p11.2 deletions (28/55) were detected with prenatal abnormal ultrasound findings. Vertebral malformations were identified as the most distinctive structural malformations and were enriched in fetuses with 16p11.2 deletions compared with controls (90.9‰ [5/55] vs. 8.4‰ [72/85,980]; P < 0.001). All 5 fetuses with vertebral malformations were confirmed to have the TBX6 haplotype of T-C-A. Overall, 47.6% (10/21) infants birthed were diagnosed with NDDs of different degrees. Language impairment was the predominant manifestation (7/10; 70.0%), followed by motor delay (5/10; 50%). Multi-omics analysis indicated that MAPK3 was the central hub of the differentially expressed gene (DEG) network. We firstly reported that histidine-associated metabolism may be the core metabolic pathway related to the 16p11.2 deletion. CONCLUSION: We demonstrated the prenatal presentation, incomplete penetrance and variable expressivity of the 16p11.2 deletion. We identified vertebral malformations were the most distinctive prenatal phenotypes, and language impairment was the predominant postnatal manifestation. Most of the 16p11.2 deletion was de novo. Meanwhile, we suggested that MAPK3 and histidine-associated metabolism may contribute to neurodevelopmental abnormalities of 16p11.2 deletion.

Human phenotype caused by biallelic KDM4B frameshift variant.

KDM4B (MIM*609765, NM_015015.3, formerly JMJD2B) encodes a histone demethylase and regulates gene expression via demethylation, mainly of H3K9 tri-methylation. Heterozygous KDM4B loss-of-function variants cause autosomal dominant intellectual developmental disorder 65 (MIM#619320), which is characterized by global developmental delay, intellectual disability, language and gross motor delays, structural brain anomalies, characteristic facial features, and clinodactyly. Although the majority of reported patients have de novo pathogenic variants, some patients inherit pathogenic variants from affected parents. To our knowledge, only 23 patients with heterozygous KDM4B variants have been reported to date, and there are no reports of patients with biallelic KDM4B pathogenic variants. Herein, we report a female patient with a biallelic KDM4B frameshift variant (NM_015015.3: c.1384_1394delinsGGG, p.(Leu462Glyfs*43)) located at exon 12 of 23 protein-coding exons, which is thought to be subject to nonsense-mediated mRNA decay and no protein production. She presented developmental and language delays and a hypotonic and characteristic face. The patient's phenotype was more obvious than that of her mother, who is heterozygous for the same variant. Although declining birth rate (embryonic lethality in male mice) in homozygous knockout mice has been demonstrated, our report suggests that homozygous KDM4B frameshift variants can be viable in humans at least female.

Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.

Structural Variations Contribute to the Genetic Etiology of Autism Spectrum Disorder and Language Impairments.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restrictive interests and/or repetitive behaviors and deficits in social interaction and communication. ASD is a multifactorial disease with a complex polygenic genetic architecture. Its genetic contributing factors are not yet fully understood, especially large structural variations (SVs). In this study, we aimed to assess the contribution of SVs, including copy number variants (CNVs), insertions, deletions, duplications, and mobile element insertions, to ASD and related language impairments in the New Jersey Language and Autism Genetics Study (NJLAGS) cohort. Within the cohort, ~77% of the families contain SVs that followed expected segregation or de novo patterns and passed our filtering criteria. These SVs affected 344 brain-expressed genes and can potentially contribute to the genetic etiology of the disorders. Gene Ontology and protein-protein interaction network analysis suggested several clusters of genes in different functional categories, such as neuronal development and histone modification machinery. Genes and biological processes identified in this study contribute to the understanding of ASD and related neurodevelopment disorders.

¿Qué puede esconder el retraso global del desarrollo? A propósito de un caso de causa genética / What can Global Developmental Delay Conceal? Apropos of a Case with a Genetic Cause

Se presenta un niño de 6 años con antecedente de retraso del lenguaje que llevó a sus padres a realizar múltiples consultas. En un primer momento, su cuadro fue interpretado como parte de un retraso global del desarrollo. Posteriormente, el paciente presentó convulsiones y episodios de descompensación metabólica, comenzando desde entonces su seguimiento por los Servicios de neurología, genética y metabolismo. Finalmente, tras varios estudios complementarios, por medio de un exoma trío se arribó al diagnóstico de síndrome de microduplicación del cromosoma 7q11.23, lo que justifica tanto el retraso global de desarrollo del paciente como su clínica neurológica. (AU)

A six-year-old boy presents with a history of language delay that led his parents to make multiple consultations. At first, we interpreted his condition as part of a global developmental delay. Subsequently, the patient presented seizures and episodes of metabolic decompensation, and since then, he had to be followed up by neurology, genetics, and metabolism services. Finally, after several complementary studies, following a trio exome analysis, we diagnosed chromosome 7q11.23 microduplication syndrome, which explains his global developmental delay and neurological symptoms. (AU)

Expansion of clinical and variant spectrum of EEF2-related neurodevelopmental disorder: Report of two additional cases.

Eukaryotic translation elongation factor 2 (eEF2), encoded by the gene EEF2, is an essential factor involved in the elongation phase of protein translation. A specific heterozygous missense variant (p.P596H) in EEF2 was originally identified in association with autosomal dominant adult-onset spinocerebellar ataxia-26 (SCA26). More recently, additional heterozygous missense variants in this gene have been described to cause a novel, childhood-onset neurodevelopmental disorder with benign external hydrocephalus. Herein, we report two unrelated individuals with a similar gene-disease correlation to support this latter observation. Patient 1 is a 7-year-old male with a previously reported, de novo missense variant (p.V28M) who has motor and speech delay, autism spectrum disorder, failure to thrive with relative macrocephaly, unilateral microphthalmia with coloboma and eczema. Patient 2 is a 4-year-old female with a novel de novo nonsense variant (p.Q145X) with motor and speech delay, hypotonia, macrocephaly with benign ventricular enlargement, and keratosis pilaris. These additional cases help to further expand the genotypic and phenotypic spectrum of this newly described EEF2-related neurodevelopmental syndrome.

The Development of Mental Health Difficulties in Young People With and Without Developmental Language Disorder: A Gene-Environment Interplay Study Using Polygenic Scores.

PURPOSE: Young people with developmental language disorder (DLD) have poorer mental health than those without DLD. However, not all young people with DLD are equally affected; some have more mental health difficulties than others. What explains these differences remains unclear. METHOD: Data from a community cohort study, the Avon Longitudinal Study of Parents and Children, were analyzed to investigate genetic and environmental influences on the development of mental health difficulties at five time points from childhood (7 years) to adolescence (16 years) in 6,387 young people (8.7% with DLD). Regression and latent class models were fitted to the data. RESULTS: Polygenic scores (PGSs), indices of genetic risk, for common psychiatric disorders (major depressive disorder, anxiety disorder, and attention deficit hyperactivity disorder) predicted mental health difficulties in both groups (with and without DLD). The presence of DLD, in some instances, amplified mental health difficulties for those with high genetic risk for common psychiatric disorders. Subgroups of children with similar developmental trajectories of mental health difficulties were identified. Young people with DLD were more likely than those without DLD to follow mental health subgroups characterized by consistently high levels of difficulties during development. PGSs, socioeconomic status, and the early home environment distinguished subgroups with low mental health difficulties from those characterized by high levels of difficulties, but these effects did not differ based on DLD status. CONCLUSIONS: These findings suggest that, for the most part, both genetic and environmental risk affect the development of mental health difficulties in a cumulative way for young people with DLD (and those without). Some analysis did, however, suggest that genetic risk for common psychiatric disorders might manifest more strongly in those with DLD compared with those without DLD. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.22351012.

Developmental language disorder - a comprehensive study of more than 46,000 individuals.

Developmental language disorder (DLD) is characterized by enduring low language abilities with a significant functional impact, in the absence of biomedical conditions in which language impairment is part of a complex of impairments. There is a lack of awareness of DLD even among healthcare professionals. Here we estimated the prevalence of DLD and its links to reading and learning difficulties and physical and mental health in the Danish Blood Donor Study (N = 46,547), where DLD-related information is based on questionnaires (self-report). We compared the questionnaire-derived DLD status with the relevant language-related diagnoses from hospital registers. We also investigated the genetic architecture of DLD in a subset of the cohort (N = 18,380). DLD was significantly associated with reading and learning difficulties and poorer mental and physical health. DLD prevalence was 3.36%-3.70% based on questionnaires, compared with 0.04% in hospital registers. Our genetic analyses identified one genome-wide significant locus, but not a significant heritability estimate. Our study shows that DLD has health-related implications that may last into adulthood, and that DLD may be undiagnosed in general healthcare. Furthermore, DLD is likely more genetically heterogeneous than narrower developmental language phenotypes. Our results emphasize the need to raise awareness of DLD and consider criteria for molecular studies of DLD to reduce case heterogeneity.

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.

CDK13-related disorder: a deep characterization of speech and language abilities and addition of 33 novel cases.

Speech and language impairments are central features of CDK13-related disorder. While pathogenic CDK13 variants have been associated with childhood apraxia of speech (CAS), a systematic characterisation of communication has not been conducted. Here we examined speech, language, non-verbal communication skills, social behaviour and health and development in 41 individuals with CDK13-related disorder from 10 countries (male = 22, median-age 7 years 1 month, range 1-25 years; 33 novel). Most participants used augmentative and alternative communication (AAC) in early childhood (24/41). CAS was common (14/22). Performance varied widely across intellectual ability, social behaviour and expressive language skills, with participants ranging from within average through to the severely impaired range. Receptive language was significantly stronger than expressive language ability. Social motivation was a relative strength. In terms of a broader health phenotype, a quarter had one or more of: renal, urogenital, musculoskeletal, and cardiac malformations, vision impairment, ear infections and/or sleep disturbance. All had gross and fine motor impairments (41/41). Other conditions included mild-moderate intellectual disability (16/22) and autism (7/41). No genotype-phenotype correlations were found. Recognition of CAS, a rare speech disorder, is required to ensure appropriately targeted therapy. The high prevalence of speech and language impairment underscores the importance of tailored speech therapy, particularly early access to AAC supports.

Expanding the neuroimaging findings of guanidinoacetate methyltransferase deficiency in an Iranian girl with a homozygous frameshift variant in the GAMT.

Guanidinoacetate methyltransferase deficiency (GAMTD) is a treatable neurodevelopmental disorder with normal or nonspecific imaging findings. Here, we reported a 14-month-old girl with GAMTD and novel findings on brain magnetic resonance imaging (MRI).A 14-||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||month-old female patient was referred to Myelin Disorders Clinic due to onset of seizures and developmental regression following routine vaccination at 4 months of age. Brain MRI, prior to initiation of treatment, showed high signal intensity in T2-weighted imaging in bilateral thalami, globus pallidus, subthalamic nuclei, substantia nigra, dentate nuclei, central tegmental tracts in the brainstem, and posterior periventricular white matter which was masquerading for mitochondrial leukodystrophy. Basic metabolic tests were normal except for low urine creatinine; however, exome sequencing identified a homozygous frameshift deletion variant [NM_000156: c.491del; (p.Gly164AlafsTer14)] in the GAMT. Biallelic pathogenic or likely pathogenic variants cause GAMTD. We confirmed the homozygous state for this variant in the proband, as well as the heterozygote state in the parents by Sanger sequencing.MRI features in GAMTD can mimic mitochondrial leukodystrophy. Pediatric neurologists should be aware of variable MRI findings in GAMTD since they would be misleading to other diagnoses.

Sex differences in early language delay and in developmental language disorder.

Developmental language disorder (DLD) is a neurodevelopmental condition, occurring in about 3% to 7% of preschoolers, that can impair communication and negatively impact educational and social attainments, in spite of adequate neurological, cognitive, emotional, social development, and educational opportunities for language learning. Significant risk factors for DLD are male sex, familial history of early language delay, low parental education, and various perinatal factors. A strong sex effect with a higher prevalence of language delay and DLD in males than in females has been consistently reported. Neurobiological and environmental risk factors, interacting with each other, are probably responsible for the phenotypic expression of DLD. The aim of this brief review is to further the knowledge of the role of sex in early language delay and DLD by analyzing the evidence from four significant sources: epidemiological studies, studies on twins, family aggregation studies, and studies on sex chromosome trisomies. Data pertaining only to sex differences (biological and physiological characteristics of females and males) will be analyzed. Studies on family aggregations and twins confirm the role of genetic factors and of sex in determining language abilities and disabilities, but genes alone do not determine outcomes. Sex chromosome trisomies represent a unique example of the relationship between a genetic alteration and a language disorder. Clarification of how sex acts in determining DLD could provide new information on early risk factors and, thus, contribute to improve diagnosis and clinical management.

A case with cardiac, skeletal, speech, and motor traits narrows the subtelomeric 19p13.3 microdeletion region to 46 kb.

Subtelomeric 19p13.3 deletions have been associated with diverse anatomical and developmental phenotypes. A recent study of eight patients with subtelomeric interstitial 19p13.3 microdeletions at 0.3-1.4 Mb (hg 19) showed associations with growth restrictions, skeletal deformities, craniofacial anomalies, congenital heart defects, renal malformations, hernias, immune system deficits, fine and gross motor delays, speech delays, and developmental and learning delays. The authors defined two small regions of overlap containing four and 11 genes, respectively, with potential haploinsufficiency. Here, we present a new case with a de novo 184 kb deletion containing eight genes, three of which fall into the second previously identified small region of overlap, reducing the shared region to 46 kb. Phenotypic traits include most of the core findings in the previously reported cases but not growth restrictions, craniofacial anomalies, renal malformation, and learning disability. A closer look at the speech and motor delays reveals apraxic speech and discoordination in the fine and gross motor domain, consistent with cerebellar involvement across motor systems. Findings are consistent with a role of AZU1 in the observed immune deficiencies and PTBP1 in the observed skeletal, abdominal, speech, language, motor, and sensory traits. This case thus contributes to a more nuanced understanding of the subtelomeric 19p13.3 deletion region.

The effect of growth hormone treatment in children with novel BPTF gene variants: A report of two cases and literature review.

BACKGROUND: Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is a rare neurodevelopmental disease caused by BPTF gene variants. To date, there are only 36 cases reported in the literature, and patients mainly presented with a developmental delay, language delay, and microcephaly. About 35% of the patients had short stature, but there had no reports published on the treatment. METHODS: The exome sequencing was performed in two probands. Sanger sequencing was used to confirm the identified variants both in probands and their parents. RESULTS: As for the Chinese population, we report two novel variants in BPTF gene (NM_004459.6: c.1133G>A, c.5941delC) causing NEDDFL from two unrelated families. Both children had short stature and responded to recombinant human growth hormone (rhGH) treatment - the first report of this therapy in NEDDFL patients. CONCLUSION: Our findings broaden the genotypic spectrum of BPTF variants. The salutary effect of rhGH in the NEDDFL is documented.

Expansion of the genotypic and phenotypic spectrum of CTCF-related disorder guides clinical management: 43 new subjects and a comprehensive literature review.

Monoallelic variants of CTCF cause an autosomal dominant neurodevelopmental disorder with a wide range of features, including impacts on the brain, growth, and craniofacial development. A growing number of subjects with CTCF-related disorder (CRD) have been identified due to the increased application of exome sequencing, and further delineation of the clinical spectrum of CRD is needed. Here, we examined the clinical features, including facial profiles, and genotypic spectrum of 107 subjects with identified CTCF variants, including 43 new and 64 previously described subjects. Among the 43 new subjects, 23 novel variants were reported. The cardinal clinical features in subjects with CRD included intellectual disability/developmental delay (91%) with speech delay (65%), motor delay (53%), feeding difficulties/failure to thrive (66%), ocular abnormalities (56%), musculoskeletal anomalies (53%), and behavioral problems (52%). Other congenital anomalies were also reported, but none of them were common. Our findings expanded the genotypic and phenotypic spectrum of CRD that will guide genetic counseling, management, and surveillance care for patients with CRD. Additionally, a newly built facial gestalt on the Face2Gene tool will facilitate prompt recognition of CRD by physicians and shorten a patient's diagnostic odyssey.

Phenotype expansion and neurological manifestations of neurobehavioural disease caused by a variant in RFX7.

The RFX7 gene is one of eight genes within the regulatory factor X family. RFX7 is highly expressed in the brain and plays an important role in cell maturation and differentiation. It has only recently been implicated in disease in humans. Reports from 15 individuals have described RFX-associated phenotype as a neurobehavioural disease, manifesting primarily with global developmental delay and intellectual disability. Autism spectrum disorder and attention deficit hyperactivity disorder have also been described in some children. Here we report a case of a 19-month-old with a de novo missense variant in RFX7 resulting in severe global developmental delay including significant speech delay, microcephaly, dyskinetic movements, and failure to thrive. This is the first association between variants in RFX7 and failure to thrive, expanding the phenotype of this newly described gene. In this report we will also show RFX7 associated progressive central nervous system involvement through serial brain imaging.

Three children with different de novo BCL11A variants and diverse developmental phenotypes, but shared global motor discoordination and apraxic speech: Evidence for a functional gene network influencing the developing cerebellum and motor and auditory cortices.

BCL11A is implicated in BCL11A-Related Intellectual Development Disorder (BCL11A-IDD). Previously reported cases had various types of BCL11A variants (copy-number variations [CNVs], singlenucleotide variants [SNVs]). Phenotypes included global, cognitive, and motor delays, autism spectrum disorder (ASD), craniofacial dysmorphology, and speech and language delays described generally, with only two reports specifying childhood apraxia of speech (CAS). Here, we present three additional children with CAS and de novo BCL11A variants, a p.Ala182Thr nonconservative missense and a p.GLu611.Ter nonsense variant, both in exon 4, and a 106 kb deletion harboring exons 1 and 2. All three children have fine and gross motor discoordination, feeding difficulties, and visual motor disorders. Intellectual and learning disabilities and disordered language skills were seen only in the child with the missense variant and the child with the deletion. These findings align with, and expand, previous findings in that BCL11A variants have significant and highly penetrant apraxic effects across motor systems, consistent with cerebellar involvement. The deletion of exons 1 and 2 is the smallest BCL11A CNV with the full phenotypic expression reported to date. The present results support previous findings in that BCL11A-IDD can result from BCL11A variants regardless of type (deletion, SNVs). A gene expression study shows that BCL11 is expressed highly in the early developing cerebellum and primary motor and auditory cortices. Significant co-expression rates in these regions with genes previously implicated in disorders of spoken language and in ASD support the phenotypic overlaps in children with BCL11A-IDD, CAS, and ASD.

The importance of deep speech phenotyping for neurodevelopmental and genetic disorders: a conceptual review.

BACKGROUND: Speech is the most common modality through which language is communicated, and delayed, disordered, or absent speech production is a hallmark of many neurodevelopmental and genetic disorders. Yet, speech is not often carefully phenotyped in neurodevelopmental disorders. In this paper, we argue that such deep phenotyping, defined as phenotyping that is specific to speech production and not conflated with language or cognitive ability, is vital if we are to understand how genetic variations affect the brain regions that are associated with spoken language. Speech is distinct from language, though the two are related behaviorally and share neural substrates. We present a brief taxonomy of developmental speech production disorders, with particular emphasis on the motor speech disorders childhood apraxia of speech (a disorder of motor planning) and childhood dysarthria (a set of disorders of motor execution). We review the history of discoveries concerning the KE family, in whom a hereditary form of communication impairment was identified as childhood apraxia of speech and linked to dysfunction in the FOXP2 gene. The story demonstrates how instrumental deep phenotyping of speech production was in this seminal discovery in the genetics of speech and language. There is considerable overlap between the neural substrates associated with speech production and with FOXP2 expression, suggesting that further genes associated with speech dysfunction will also be expressed in similar brain regions. We then show how a biologically accurate computational model of speech production, in combination with detailed information about speech production in children with developmental disorders, can generate testable hypotheses about the nature, genetics, and neurology of speech disorders. CONCLUSIONS: Though speech and language are distinct, specific types of developmental speech disorder are associated with far-reaching effects on verbal communication in children with neurodevelopmental disorders. Therefore, detailed speech phenotyping, in collaboration with experts on pediatric speech development and disorders, can lead us to a new generation of discoveries about how speech development is affected in genetic disorders.