PGAP2-Related Hyperphosphatasia-Mental Retardation Syndrome: Report of a Novel Patient, Toward a Broadening of Phenotypic Spectrum and Therapeutic Perspectives.

PGAP2 gene has been known to be the cause of "hyperphosphatasia, mental retardation syndrome-3" (HPMRS3). To date, 14 pathogenic variants in PGAP2 have been identified as the cause of this syndrome in 24 patients described in single-case reports or small clinical series with pan-ethnic distribution. We aim to present a pediatric PGAP2-mutated case, intending to further expand the clinical phenotype of the syndrome and to report our experience on a therapeutic approach to drug-resistant epilepsy.We present the clinical, neuroradiological, and genetic characterization of a Caucasian pediatric subject with biallelic pathogenic variants in the PGAP2 gene revealed by next generation sequencing analysis.We identified a subject who presented with global developmental delay and visual impairment. Brain magnetic resonance imaging showed mild hypoplasia of the inferior cerebellar vermis and corpus callosum and mild white matter reduction. Laboratory investigations detected an increase in alkaline phosphatase. At the age of 13 months, he began to present epileptic focal seizures with impaired awareness, which did not respond to various antiseizure medications. Electroencephalogram (EEG) showed progressive background activity disorganization and multifocal epileptic abnormalities. Treatment with high-dose pyridoxine showed partial benefit, but the persistence of seizures and the lack of EEG amelioration prompted us to introduce ketogenic diet treatment.Our case provides a further phenotypical expansion of HPMRS3 to include developmental and epileptic encephalopathy. Due to the limited number of patients reported so far, the full delineation of the clinical spectrum of HPMRS3 and indications for precision medicine would benefit from the description of new cases and their follow-up evaluations.

Splicing Factor PQBP1 Curtails BAX Expression to Promote Ovarian Cancer Progression.

Splicing factor polyglutamine binding protein-1 (PQBP1) is abundantly expressed in the central nervous system during development, and mutations in the gene cause intellectual disability. However, the roles of PQBP1 in cancer progression remain largely unknown. Here, it is shown that PQBP1 overexpression promotes tumor progression and indicates worse prognosis in ovarian cancer. Integrative analysis of spyCLIP-seq and RNA-seq data reveals that PQBP1 preferentially binds to exon regions and modulates exon skipping. Mechanistically, it is shown that PQBP1 regulates the splicing of genes related to the apoptotic signaling pathway, including BAX. PQBP1 promotes BAX exon 2 skipping to generate a truncated isoform that undergoes degradation by nonsense-mediated mRNA decay, thus making cancer cells resistant to apoptosis. In contrast, PQBP1 depletion or splice-switching antisense oligonucleotides promote exon 2 inclusion and thus increase BAX expression, leading to inhibition of tumor growth. Together, the results demonstrate an oncogenic role of PQBP1 in ovarian cancer and suggest that targeting the aberrant splicing mediated by PQBP1 has therapeutic potential in cancer treatment.

Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.

Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.

Pathogenic heterozygous loss of function variants in CTNNB1 are associated with CTNNB1 neurodevelopmental disorder. We report the clinical phenotype of individuals with CTNNB1 neurodevelopmental disorder using both caregiver-reported data (medical history, adaptive function, quality of life, and behavior issues) and in-person clinical assessments (neurological, motor, and cognitive function) in 32 individuals with likely pathogenic or pathogenic CTNNB1 variants. Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord. Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy. Half of individuals walked without an assistive device. The mean Gross Motor Functional Measure-66 score was 56.6 (SD = 14.8). Average time to complete Nine-Hole Peg Test was slower than norms. Mean general conceptual ability composite scores from Differential Ability Scales Second Edition were very low (M = 58.3, SD = 11.3). Fifty-five percent of individuals had low adaptive functioning based on the Vineland Adaptive Behavioral Scales. Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges. The mean overall Quality of Life Inventory-Disability score was 81.7 (SD = 11.9). These data provide a detailed characterization of clinical features in individuals with CTNNB1 neurodevelopmental disorder.

Genetic and phenotypic findings in 34 novel Spanish patients with DDX3X neurodevelopmental disorder.

DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate immunity, apoptosis and tumorigenesis. Variants in DDX3X have been associated with a developmental disorder named intellectual developmental disorder, X-linked syndromic, Snijders Blok type (MRXSSB, MIM #300958) or DDX3X neurodevelopmental disorder (DDX3X-NDD). DDX3X-NDD is mainly characterized by intellectual disability, brain abnormalities, hypotonia and behavioral problems. Other common findings include gastrointestinal abnormalities, abnormal gait, speech delay and microcephaly. DDX3X-NDD is predominantly found in females who carry de novo variants in DDX3X. However, hemizygous pathogenic DDX3X variants have been also found in males who inherited their variants from unaffected mothers. To date, more than 200 patients have been reported in the literature. Here, we describe 34 new patients with a variant in DDX3X and reviewed 200 additional patients previously reported in the literature. This article describes 34 additional patients to those already reported, contributing with 25 novel variants and a deep phenotypic characterization. A clinical review of our cohort of DDX3X-NDD patients is performed comparing them to those previously published.

New cases of recently described Thauvin-Robinet-Faivre syndrome with a novel homozygous FIBP gene variant.

Thauvin-Robinet-Faivre syndrome (#617107) is a rare autosomal recessive overgrowth syndrome characterized by intellectual disability, facial dysmorphism, macrocephaly, and variable congenital malformations. It is caused by homozygous or compound heterozygous FIBP gene mutations. The FIBP gene is located on the 11q13.1 region and codes the acidic fibroblast growth factor intracellular binding protein, which is involved in the fibroblast growth factor (FGF) signaling pathway. FGF signaling is required for neurogenesis and neuronal precursor proliferation. The FGF controls cell proliferation, differentiation, and migration in embryonic development and in adult life. Overgrowth syndromes consist of a wide spectrum disorders characterized by prenatal and postnatal excess growth in weight and length, often associated malformations, intellectual disability, and neoplastic predisposition. Embryonic tumors are especially common in these syndromes. Thauvin-Robinet-Faivre syndrome is a recently described overgrowth syndrome with typical facial dysmorphic and clinical features. To date, only four patients have been reported with this disorder. Herein, two new cases of Thauvin-Robinet-Faivre syndrome are reported with overgrowth, intellectual disability, typical dysmorphic signs in one dysplastic kidney, and a novel homozygous FIBP gene variant. Exome sequencing analysis showed that both affected siblings share the same homozygous c. 412-3_415dupCAGTTTG FIBP gene variant. Reporting two new cases with this rare autosomal recessive overgrowth syndrome with a novel FIBP gene variant will support and expand the clinical spectrum of Thauvin-Robinet-Faivre syndrome. Also discussed will be the function of FIBP in tumorigenesis and the possible renal tumor susceptibility in heterozygous carriers will be emphasized.

Further characterisation of ARX-related disorders in females due to inherited or de novo variants.

The Aristaless-related homeobox (ARX) gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of ARX-related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in ARX families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants. In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo ARX pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited variants (n=33) or variants of unknown inheritance (n=20). Altogether, the clinical spectrum of females with heterozygous pathogenic ARX variants is broad: 42.5% are asymptomatic, 16.4% have isolated agenesis of the corpus callosum (ACC) or mild symptoms (learning disabilities, autism spectrum disorder, drug-responsive epilepsy) without ID, whereas 41% present with a severe phenotype (ie, ID or developmental and epileptic encephalopathy (DEE)). The ID/DEE phenotype was significantly more prevalent in females carrying de novo variants (75%, n=15/20) versus in those carrying inherited variants (27.3%, n=9/33). ACC was observed in 66.7% (n=24/36) of females who underwent a brain MRI. By refining the clinical spectrum of females carrying ARX pathogenic variants, we show that ID is a frequent sign in females with this X linked condition.

Woodhouse-Sakati syndrome in an Indian patient with a novel pathogenic variant.

Woodhouse-Sakati syndrome consists of hypogonadism, diabetes mellitus, alopecia, ECG abnormalities, and dystonia. This condition is caused by the loss of function of the DCAF17 gene. Most of the patients have been reported from Greater Middle Eastern countries. We report a 38 male from southern India who presented with syncope and massive hemoptysis due to ruptured bronchopulmonary collaterals. He also had alopecia, cataracts, recently diagnosed diabetes and hypogonadism. Whole exome sequencing showed a novel homozygous truncating variant in the DCAF17 gene. Despite embolization of the aortopulmonary collaterals, the patient died of recurrent hemoptysis.

Expanding the phenotype of Brunner syndrome from childhood to adulthood: Description of the second pediatric patient and his mother.

Brunner syndrome is a recessive X-linked disorder caused by pathogenic variants in the monoamine oxidase A gene (MAOA). It is characterized by distinctive aggressive behavior, mild intellectual disability, sleep disturbances, and typical biochemical alterations deriving from the impaired monoamine metabolism. We herein describe a 5-year-old boy with developmental delay, autistic features, and myoclonic epilepsy, and his mother, who had mild intellectual disability and recurrent episodes of palpitations, headache, abdominal pain, and abdominal bloating. Whole exome sequencing allowed detection of the maternally-inherited variant c.410A>G, (p.Glu137Gly) in the MAOA gene. The subsequent biochemical studies confirmed the MAOA deficiency both in the child and his mother. Given the serotonergic symptoms associated with high serotonin levels found in the mother, treatment with a serotonin reuptake inhibitor and dietary modifications were carried out, resulting in regression of the biochemical abnormalities and partial reduction of symptoms. Our report expands the phenotypic spectrum of Brunner disease, bringing new perspectives on the behavioral and neurodevelopmental phenotype from childhood to adulthood.

A severe neurocognitive phenotype caused by biallelic CHD3 variants in two siblings.

CHD3 heterozygous variants are associated with Snijders Blok-Campeau syndrome (SBCS) which consists of intellectual disability (ID), macrocephaly, and dysmorphic facies. Most reported variants are missense or loss of function clustered within the ATPase/helicase domain of the protein. We report a severe neurocognitive phenotype caused by biallelic CHD3 variants in two siblings, each inherited from a mildly affected parent. Male and female siblings were referred to the Genetics Clinic due to severe ID and profound dysmorphism. The parents are first cousins of Iranian descent with borderline intellectual abilities. Exome sequencing was performed for the affected female and her parents. A single homozygous candidate variant in the CHD3 gene was detected in the proband: c.5384_5389dup. p.Arg1796_Phe1797insTrpArg, resulting in an in-frame insertion of 2 amino acids located outside the ATPase/helicase domain at the C-terminal region of CHD3-encoding residues. This variant is classified as likely pathogenic according to ACMG guidelines. The variant was detected in a heterozygous state in each parent. Both affected siblings were homozygous, while their unaffected brother did not carry the variant. Biallelic CHD3 variants cause a severe neurodevelopmental syndrome that is distinguishable from SBCS. We assume that the variant type (in-frame insertion) and location may enable CHD3 biallelic variants.

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.

Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12 -year-old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin-Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results.

Duplication at 19q13.32q13.33 Segregating with Neuropsychiatric Phenotype in a Three-Generation Family: Towards the Definition of a Critical Region.

Chromosomal submicroscopic imbalances represent well-known causes of neurodevelopmental disorders. In some cases, these can cause specific autosomal dominant syndromes, with high-to-complete penetrance and de novo occurrence of the variant. In other cases, they result in non-syndromic neurodevelopmental disorders, often acting as moderate-penetrance risk factors, possibly inherited from unaffected parents. We describe a three-generation family with non-syndromic neuropsychiatric features segregating with a novel 19q13.32q13.33 microduplication. The propositus was a 28-month-old male ascertained for psychomotor delay, with no dysmorphic features or malformations. His mother had Attention-Deficit/Hyperactivity Disorder and a learning disability. The maternal uncle had an intellectual disability. Chromosomal microarray analysis identified a 969 kb 19q13.32q13.33 microduplication in the proband. The variant segregated in the mother, the uncle, and the maternal grandmother of the proband, who also presented neuropsychiatric disorders. Fragile-X Syndrome testing was negative. Exome Sequencing did not identify Pathogenic/Likely Pathogenic variants. Imbalances involving 19q13.32 and 19q13.33 are associated with neurodevelopmental delay. A review of the reported microduplications allowed to propose BICRA (MIM *605690) and KPTN (MIM *615620) as candidates for the neurodevelopmental delay susceptibility in 19q13.32q13.33 copy number gains. The peculiarities of this case are the small extension of the duplication, the three-generation segregation, and the full penetrance of the phenotype.

A Novel Neuroimaging Phenotype in the X-Linked Intellectual Disability with a Missense Mutation of CNKSR2 Gene.

Background: Mental retardation, X-linked, syndromic, Houge type (MRXSHG) is a form of mental retardation characterized by intellectual disability, speech and language impairments, and early-onset seizures. It has been recently recorded in Online Mendelian Inheritance in Man (OMIM), and only 10 cases have been reported in the literature so far. Objective: To highlight the novel neuroimaging findings in the pediatric X-linked intellectual disability with a missense mutation of connector enhancer of kinase suppressor of RAS2 (CNKSR2) gene. Material and Methods: We present a case of intellectual disability, refractory epilepsy, speech and language delay with subtle dysmorphism, and behavioral issues in an 11-year-old boy with novel neuroimaging findings in a CNKSR2 gene with missense mutation. Results: Brain MRI revealed involvement of the basal ganglia, predominantly the neostriatum, and along with the subependymal aspects with focal cavitations involving, especially the bilateral caudate heads. There was relative sparing of the globus pallidi and posterior putamina bilaterally. Whole-exome sequencing identified a hemizygous missense pathogenic variant in the CNKSR2 gene. The mother was found to be an asymptomatic carrier. Conclusion: This case report highlights the rare missense mutation in the CNKSR2 gene and abnormal neuroimaging findings, which further provide information about the phenotypic characteristics of X-linked syndromic intellectual disability.

From Feeding Challenges to Oral-Motor Dyspraxia: A Comprehensive Description of 10 New Cases with CTNNB1 Syndrome.

CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-score equivalent was 43.1 ± 7.5. These findings contribute to the understanding of the CTNNB1 syndrome highlighting the oral motor phenotype, and correlating specific gene variants with clinical characteristics.

Identification of a Novel FOXP1 Variant in a Patient with Hypotonia, Intellectual Disability, and Severe Speech Impairment.

The FOXP subfamily includes four different transcription factors: FOXP1, FOXP2, FOXP3, and FOXP4, all with important roles in regulating gene expression from early development through adulthood. Haploinsufficiency of FOXP1, due to deleterious variants (point mutations, copy number variants) disrupting the gene, leads to an emerging disorder known as "FOXP1 syndrome", mainly characterized by intellectual disability, language impairment, dysmorphic features, and multiple congenital abnormalities with or without autistic features in some affected individuals (MIM 613670). Here we describe a 10-year-old female patient, born to unrelated parents, showing hypotonia, intellectual disability, and severe language delay. Targeted resequencing analysis allowed us to identify a heterozygous de novo FOXP1 variant c.1030C>T, p.(Gln344Ter) classified as likely pathogenetic according to the American College of Medical Genetics and Genomics guidelines. To the best of our knowledge, our patient is the first to date to report carrying this stop mutation, which is, for this reason, useful for broadening the molecular spectrum of FOXP1 clinically relevant variants. In addition, our results highlight the utility of next-generation sequencing in establishing an etiological basis for heterogeneous conditions such as neurodevelopmental disorders and providing additional insight into the phenotypic features of FOXP1-related syndrome.

Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re-classification of an ARID1B missense variant.

Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.

MTSS2-related neurodevelopmental disorder: Further delineation of the phenotype.

MTSS2-related neurodevelopmental disorder (MTSS2-related NDD) (MIM 620086) is characterized by intellectual developmental disorder with ocular anomalies and distinctive facial features (IDDOF). The only existing report to date described five individuals who exhibited an identical de novo c.2011C>T (p.Arg671Trp) variant in the MTSS2 gene. Herein, we report a new case of MTSS2-related NND in a male dizygotic twin who presented with IDDOF and severe intellectual disability. This patient also displayed additional clinical features, including low functioning autism, hypothyroidism, duodenal obstruction secondary to Ladd's bands, inguinal hernias, cryptorchidism, transient subperiosteal new bone formation, and short stature with delayed bone age, which had not been previously reported in association with the MTSS2-related NDD. Exome sequencing identified the recurrent c.2011C>T (p.Arg671Trp) variant in the MTSS2 gene. The mother and the other twin tested negative for the pathogenic variant, while the father's participation in the study was unavailable. This case confirms that the MTSS2-related NDD is caused by the recurrent MTSS2 missense variant p.Arg671Trp. The novel findings identified in our patient expand the phenotypic spectrum associated with this new autosomal dominant entity, but further studies on its genetic and clinical manifestations are still needed.

Defining the phenotype of PGAP3-congenital disorder of glycosylation; a review of 65 cases.

Biallelic pathogenic variants in PGAP3 cause a rare glycosylphosphatidyl-inositol biogenesis disorder, PGAP3-CDG. This multisystem condition presents with a predominantly neurological phenotype, including developmental delay, intellectual disability, seizures, and hyperphosphatemia. Here, we summarized the phenotype of sixty-five individuals including six unreported individuals from our CDG natural history study with a confirmed PGAP3-CDG diagnosis. Common additional features found in this disorder included brain malformations, behavioral abnormalities, cleft palate, and characteristic facial features. This report aims to review the genetic and metabolic findings and characterize the disease's phenotype while highlighting the necessary clinical approach to improve the management of this rare CDG.

Expanding the mutational spectrum of ZTTK syndrome: A de novo variant with global developmental delay and malnutrition in a Chinese patient.

BACKGROUND: Zhu-Tokita-Takenouchi-Kim (ZTTK, OMIM 617140) syndrome is a severe multisystem developmental disorder characterized by intellectual disability, developmental delay, cortical malformations, epilepsy, visual problems, musculoskeletal abnormalities, and congenital malformations. ZTTK syndrome is caused by a heterozygous pathogenic variant of the SON gene (NM_138927) at chromosome 21q22.1. The purpose of this study was to investigate the pathogenesis of a 6-month-old Chinese child who exhibited global developmental delay, muscle weakness, malnutrition, weight loss, and strabismus, brain abnormality, immunological system abnormalities. METHODS: The little girl was tested for medical exome sequencing (MES) and mtDNA sequencing in trio. And, the mutation was validated by Sanger sequencing. RESULTS: A novel de novo frameshift variant, c.1845_1870del26 (p.G616Sfs*61), in the SON gene was found in the proband. CONCLUSION: We described a 6-month-old Chinese child with global developmental delay caused by pathogenic de novo mutation c.1845_1870del26 (p.G616Sfs*61) in the SON. Apart from a founder mutation, we reviewed the phenotypic abnormalities and genotypes in 79 individuals. The data showed that global developmental delay is accompanied by other system disorders. Our findings expanded the mutational spectrum of ZTTK syndrome and provide genetic counseling of baby with global developmental delay.