TRAPPC9-related neurodevelopmental disorder: Report of a homozygous deletion in TRAPPC9 due to paternal uniparental isodisomy

TRAPPC9 loss-of-function biallelic variants are associated with an autosomal recessive intellectual disability syndrome (Online Mendelian Inheritance of Man no. 613192), also characterized by microcephaly, hypertelorism, obesity, growth delay, and behavioral differences. Here, we describe an 8-year-old Hispanic female with neurodevelopmental disorder, partial epilepsy, microcephaly, bilateral cleft lip and alveolus, growth delay, and dysmorphic features. She had abnormal myelination, mega cisterna magna, and colpocephaly on brain magnetic resonance imaging (MRI). Microarray showed a single ~146 Mb region of homozygosity (ROH) encompassing all of Chromosome 8, consistent with uniparental isodisomy (UPD). Exome sequencing performed in-house did not identify single nucleotide variants to explain her phenotype. Algorithms developed in-house and further evaluation of BAM files revealed a homozygous deletion overlapping Exon 2 in TRAPPC9 within the ROH. Subsequent del/dup analyses with exon-level oligo array confirmed a likely pathogenic deletion in TRAPPC9 (NM_031466.5): arr[GRCh37] 8q24.3(141460661_141461780)x0. Our case highlights the implications of downstream analyses from UPD/ROH given the increased risk for AR conditions, the strengths of combining orthologous molecular methods to establish a diagnosis and further delineates the TRAPPC9-related phenotype in an individual of Hispanic ancestry.     

ZDHHC9 X-linked intellectual disability: Clinical and molecular characterization

The ZDHHC9 gene encodes the Zinc Finger DHHC-Type Containing 9 protein that functions as a palmitoyltransferase. Variants in this gene have been reported as the cause of Raymond-type X-linked intellectual disability with only 16 families described in the literature. This study reviews molecular and clinical data from previously reported patients and reports the case of a 13-year-old patient with a splicing variant in ZDHHC9 presenting intellectual disability, developmental delay, facial dysmorphisms, and skeletal defects. Although intellectual disability and developmental delay with severe speech delay have been reported in all cases with available clinical data, the remaining clinical signs differ significantly between patients. Missense, nonsense, frameshift, and splicing variants, in addition to large exonic deletions, have been described suggesting a loss of function mechanism. Though variants are distributed in almost all exons, most missense and nonsense variants affect arginine residues located in the cytoplasmic domains of this transmembrane protein, suggesting possible mutational hotspots.     

Identification of disease-causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next-generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families. By collecting clinical information on these families and comparing their phenotypes with previously reported patients, we further describe the clinical variability of ARID resulting from alterations in the EXOSC gene family, and emphasize the role of RNA processing dysregulation in ARID.     

Clinical characterization,genetic mapping and whole-genome sequence analysis of a novel autosomal recessive intellectual disability syndrome

We identified six patients presenting with a strikingly similar clinical phenotype of profound syndromic intellectual disability of unknown etiology. All patients lived in the same village. Extensive genealogical work revealed that the healthy parents of the patients were all distantly related to a common ancestor from the 17th century, suggesting autosomal recessive inheritance. In addition to intellectual disability, the clinical features included hypotonia, strabismus, difficulty to fix the eyes to an object, planovalgus in the feet, mild contractures in elbow joints, interphalangeal joint hypermobility and coarse facial features that develop gradually during childhood. The clinical phenotype did not fit any known syndrome. Genome-wide SNP genotyping of the patients and genetic mapping revealed the longest shared homozygosity at 3p22.1-3p21.1 encompassing 11.5 Mb, with no other credible candidate loci emerging. Single point parametric linkage analysis showed logarithm of the odds score of 11 for the homozygous region, thus identifying a novel intellectual disability predisposition locus. Whole-genome sequencing of one affected individual pinpointed three genes with potentially protein damaging homozygous sequence changes within the predisposition locus: transketolase (TKT), prolyl 4-hydroxylase transmembrane (P4HTM), and ubiquitin specific peptidase 4 (USP4). The changes were found in heterozygous form with 0.3–0.7% allele frequencies in 402 whole-genome sequenced controls from the north-east of Finland. No homozygotes were found in this nor additional control data sets. Our study facilitates clinical and molecular diagnosis of patients with this novel autosomal recessive intellectual disability syndrome. However, further studies are needed to unambiguously identify the underlying genetic defect.     

Identification of C12orf4 as a gene for autosomal recessive intellectual disability

Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034‐429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co‐segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub‐isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID.     

Autosomal recessive congenital cataract,intellectual disability phenotype linked to STX3 in a consanguineous Tunisian family

The aim of this study is to investigate the genetic basis of autosomal recessive congenital cataract and intellectual disability phenotype in a consanguineous Tunisian family. The whole genome scan of the studied family was performed with single nucleotide polymorphisms (SNPs). The resulted runs of homozygosity (ROH) were analyzed through the integrated Systems Tool for Eye gene discovery (iSyTE) in order to prioritize candidate genes associated with congenital cataract. Selected genes were amplified and sequenced. Bioinformatic analysis was conducted to predict the function of the mutant gene. We identified a new specific lens gene named syntaxin 3 linked to the studied phenotype. The direct sequencing of this gene revealed a novel missense mutation c.122A>G which results in p.E41G. Bioinformatic analysis suggested a deleterious effect of this mutation on protein structure and function. Here, we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability.     

A homozygous mutation in CMAS causes autosomal recessive intellectual disability in a Kazakh family

Intellectual disability (ID) describes a wide range of serious human diseases caused by defects in central nervous system development and function. Some mutant genes have been found to be associated with these diseases, but not all cases can be explained, thus suggesting that other disease-causing genes have not yet been discovered. Sialic acid is involved in a number of key biological processes, including embryo formation, nerve cell growth, and cancer cell metastasis, and very recently it has been suggested that N-acetylneuraminic acid synthase-mediated synthesis of sialic acid is required for brain and skeletal development. CMP-sialic acid synthetase (CMAS) is one of four enzymes involved in NeuNAc metabolism, as it catalyzes the formation of CMP-NeuNAc. Before the present study, no links between mutations in CMAS and incidences of human ID had been reported. In the current study, we recruited a recessive nonsyndromic ID pedigree with consanguineous marriage in which all patients have typical clinical manifestations of ID. We identified the NM_018686.3:c.563G > A (p.Arg188His) substitution in CMAS as being responsible for the disease in this family. Conservation analysis, structural prediction, and enzyme activity experiments demonstrated that (p.Arg188His) influences protein dimerization and alters CMAS enzyme activity. Our results offer a new orientation for future research and clinical diagnosis.     

TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability

PurposeTRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.MethodsExome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients’ blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics.ResultsAll 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites.ConclusionWe identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.     

A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly

Autosomal recessive intellectual disability is believed to be particularly prevalent in highly consanguineous populations and genetic isolates and may account for a quarter of all non-syndromic cases. Mutations in more than 50 genes have been reported to be involved in autosomal recessive intellectual disability, including TRAPPC9 (MIM 611966), mutations of which have been identified in six families from different geographical origins. We performed a clinical and molecular genetic study of a consanguineous Pakistani family segregating intellectual disability and microcephaly. SNP-array-based homozygosity mapping revealed suggestive linkage to four genomic regions including one on chromosome 8 that contained TRAPPC9. We detected a homozygous TRAPPC9 splice donor site mutation (c.1024+1G>T) that cosegregated with intellectual disability in the family and led to skipping of exon 3 and exons 3 and 4 in blood-derived patient RNA. We have thus identified a novel splice site mutation leading to exon skipping and premature termination of TRAPPC9 translation. These data further suggest that TRAPPC9 mutations –unlike mutations in the vast majority of the known intellectual disability-associated genes– constitute a more frequent cause of autosomal-recessive cognitive deficits, especially when microcephaly is also present.     

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and ‘pure'' forms of HSP account for ∼80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.     

Female‐restricted syndromic intellectual disability in a patient from Thailand

Female‐restricted syndromic intellectual disability (ID) is a neurodevelopmental disorder with developmental delay (DD)/ID, facial dysmorphism, and diverse congenital anomalies comprising heart defects, anal anomalies, choanal atresia, postaxial polydactyly, scoliosis, and brain abnormalities. Loss‐of‐function mutations in the USP9X gene inherited as X‐linked dominance were identified as its etiology in females of different ethnic groups. Here, we report a 15‐year‐old Thai girl harboring a novel de novo heterozygous one‐base pair deletion (c.3508delG, p.Val1170TrpfsX9) in exon 23 of USP9X. Her profound DD, dysmorphic face including attached earlobes, short stature, and congenital malformations including s‐shaped thoracolumbar scoliosis, hip dislocation, and generalized brain atrophy shared common characteristics of X‐linked syndromic ID. We have observed severely malformed oro‐dental organs and a choledochal cyst, which have never been reported. Our study presents the first patient from Thailand expanding the phenotypic and mutational spectra of the syndrome.     

HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.     

Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability

Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C.     

Expanding the phenotypic spectrum of MBOAT7‐related intellectual disability

MBOAT7 gene pathogenic variants are a newly discovered and rare cause for intellectual disability, autism spectrum disorder (ASD), seizures, truncal hypotonia, appendicular hypertonia, and below average head sizes (ranging from ?1 to ?3 standard deviations). There have been only 16 individuals previously reported who have MBOAT7‐related intellectual disability, all of whom were younger than 10 years old and from consanguineous relationships. Thus, there is a lack of phenotypic information for adolescent and adult individuals with this disorder. Medical genetics and psychiatric evaluations in a 14‐year‐old female patient with a history of global developmental delay, intellectual disability, overgrowth with macrocephaly, metrorrhagia, seizures, basal ganglia hyperintensities, nystagmus, strabismus with amblyopia, ASD, anxiety, attention deficit hyperactivity disorder (ADHD), aggressive outbursts, and hyperphagia included a karyotype, methylation polymerase chain reaction for Prader‐Willi/Angelman syndrome, chromosome microarray, and whole exome sequencing (WES), ADOS2, and ADI‐R. WES identified a homozygous, likely pathogenic variant in the MBOAT7 gene (c.855‐2A>G). This is the oldest known patient with MBOAT7‐related intellectual disability, whose unique features compared with previously described individuals include overgrowth with macrocephaly, metrorrhagia, ophthalmological abnormalities, basal ganglia hyperintensities, unspecified anxiety disorder, and ADHD; combined type; and hyperphagia with the absence of appendicular hypertonia and cortical atrophy. More individuals need to be identified in order to delineate the full clinical spectrum of this disorder.     

A homozygous stop gain mutation in BOD1 gene in a Lebanese patient with syndromic intellectual disability

Intellectual disability (ID) is a neurodevelopmental disorder characterized by limitations in both intellectual and behavioral functioning. It can occur in non-syndromic and syndromic forms involving multiple organs. While the majority of genetic variants linked to ID are de novo, inherited variants are also detected in some forms. Here, we report a consanguineous Lebanese family presenting with an autosomal recessive syndromic ID characterized by neurodevelopmental delay, mild dysmorphic features, hearing impairment and endocrine dysfunction. Whole exome sequencing enabled the detection of the homozygous nonsense mutation in BOD1, p.R151X, in the proband. BOD1 is required for chromosomes biorientation during cell division. It also contributes to the regulation of cell survival and to the modulation of fatty acid metabolism. Another nonsense mutation in BOD1 was linked to ID in a consanguineous Iranian family. This is the second report of BOD1 mutations in humans and the first in a syndromic ID including gonadal dysfunction and high-frequency hearing impairment. Our findings confirm the involvement of BOD1 in cognitive functioning and expand the clinical spectrum of BOD1 deficiency.