EMC10 homozygous variant identified in a family with global developmental delay,mild intellectual disability,and speech delay

In recent years, several genes have been implicated in the variable disease presentation of global developmental delay (GDD) and intellectual disability (ID). The endoplasmic reticulum membrane protein complex (EMC) family is known to be involved in GDD and ID. Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders. EMC10 is a bone marrow-derived angiogenic growth factor that plays an important role in infarct vascularization and promoting tissue repair. However, this gene has not been previously associated with human disease. Herein, we describe a Saudi family with two individuals segregating a recessive neurodevelopmental disorder. Both of the affected individuals showed mild ID, speech delay, and GDD. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify candidate genes. Further, to elucidate the functional effects of the variant, quantitative real-time PCR (RT-qPCR)-based expression analysis was performed. WES revealed a homozygous splice acceptor site variant (c.679-1G>A) in EMC10 (chromosome 19q13.33) that segregated perfectly within the family. RT-qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients, indicating the pathogenicity of the identified variant. For the first time in the literature, the EMC10 gene variant was associated with mild ID, speech delay, and GDD. Thus, this gene plays a key role in developmental milestones, with the potential to cause neurodevelopmental disorders in humans.     

DOCK3‐related neurodevelopmental syndrome: Biallelic intragenic deletion of DOCK3 in a boy with developmental delay and hypotonia

Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6–12 of the DOCK3 gene at 3p21.2. Symptoms of our proband resembles a phenotype of Dock3 knockout mice exhibiting sensorimotor impairments. Furthermore, our proband has clinical similarities with two siblings with compound heterozygous loss‐of‐function mutations of DOCK3 reported in [Helbig, Mroske, Moorthy, Sajan, and Velinov ( 2017 ); https://doi.org/10.1111/cge.12995 ]. Biallelic DOCK3 mutations cause a neurodevelopmental disorder characterized by unsteady gait, hypotonia, and developmental delay.     

Unilateral radio-ulnar synostosis,generalized hypotonia,developmental retardation,and a characteristic facial appearance in sibs: A new syndrome

We report on 2 sibs with generalized hypotonia, developmental retardation, unilateral radio-ulnar synostosis, and a characteristic facial appearance. We propose that they have a new autosomal recessive syndrome. © 1992 Wiley-Liss, Inc.     

A 137‐kb deletion within the Potocki–Shaffer syndrome interval on chromosome 11p11.2 associated with developmental delay and hypotonia

Potocki–Shaffer syndrome (PSS) is a rare disorder caused by haploinsufficiency of genes located on the proximal short arm of chromosome 11 (11p11.2p12). Classic features include biparietal foramina, multiple exostoses, profound hypotonia, dysmorphic features, and developmental delay/intellectual disability. Fewer than 40 individuals with PSS have been reported, with variable clinical presentations due in part to disparity in deletion sizes. We report on a boy who presented for initial evaluation at age 13 months because of a history of developmental delay, hypotonia, subtle dysmorphic features, and neurobehavioral abnormalities. SNP microarray analysis identified a 137 kb deletion at 11p11.2, which maps within the classically defined PSS interval. This deletion results in haploinsufficiency for all or portions of six OMIM genes: SLC35C1, CRY2, MAPK8IP1, PEX16, GYLTL1B, and PHF21A. Recently, translocations interrupting PHF21A have been associated with intellectual disability and craniofacial anomalies similar to those seen in PSS. The identification of this small deletion in a child with developmental delay and hypotonia provides further evidence for the genetic basis of developmental disability and identifies a critical region sufficient to cause hypotonia in this syndrome. Additionally, this case illustrates the utility of high resolution genomic approaches in correlating clinical phenotypes with specific genes in contiguous gene deletion syndromes. © 2012 Wiley Periodicals, Inc.     

Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene

Around 6% of infants born to mothers taking anticonvulsants have malformations, including neural tube defects, and a further proportion show developmental delay in later childhood. Three commonly used anticonvulsants, carbamazepine, phenytoin and sodium valproate, interfere with folic acid metabolism. We investigated the common 677 C>T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in samples from 57 patients and their parents and 152 controls to determine its contribution to the risk of fetal anticonvulsant syndrome. The 677 C>T mutation frequency was significantly higher in the mothers than in the controls, but there was no significant difference in 677 C>T frequency in the patients or in the fathers. Genotype frequencies in the mothers were significantly different from controls, there being an excess of 677 C>T homozygotes. Amongst the patients, there was an apparent excess of heterozygotes (not statistically significant), and the fathers were not significantly different from controls. Mutation in the MTHFR gene in a mother taking sodium valproate, phenytoin or carbamazepine during pregnancy is associated with fetal anticonvulsant syndrome in her offspring. The skewed distribution of genotypes in the affected children probably reflects the association of fetal anticonvulsant syndrome with the maternal genotype.     

Detection of a common mutation in the RSH or Smith‐Lemli‐Opitz syndrome by a PCR‐RFLP assay: IVS8‐1G → C is found in over sixty percent of US propositi

The RSH or Smith‐Lemli‐Opitz syndrome (SLOS) is a relatively common autosomal recessive disorder of cholesterol biosynthesis resulting from a deficiency of the enzyme 7‐dehydrocholesterol Δ7‐reductase (7‐DHCR). Mutations in 7‐DHCR gene cause SLOS. Among these, a G → C transversion in the splice acceptor site of exon 9 (IVS8‐1G → C) was suspected to be a frequent mutation, having been detected in about 18% of SLOS patients so far. This mutation results in the elimination of a AIwN1 restriction endonuclease site. We report a simple PCR‐RFLP assay to detect the IVS8‐1 G → C mutation. Using this method, we identified the IVS8‐1G → C mutation in 21 of 33 SLOS propositi. This mutation was detected in one of 90 normal adult Caucasian Americans; but not among 121 Africans from Sierra Leone, 120 Caucasians from Finland, 95 Chinese or 103 Japanese adults. The results of this study provide further evidence that IVS8‐1G → C transversion is a very common mutation in SLOS patients from the US and that the carrier rate in US caucasians may be high. The simple PCR‐RFLP assay developed makes identification of this mutation convenient for diagnosis and for carrier detection. Am. J. Med. Genet. 90:347–350, 2000 © 2000 Wiley‐Liss, Inc.     

A PUS7 gene pathogenic variant causing self-injurious behavior,sleep disturbances,and developmental delay: A case report

PUS7 gene pathogenic variants cause a deficiency in an RNA-independent pseudouridine synthase, which results in a neurodevelopmental phenotype characterized by various degrees of psychomotor delay, acquired microcephaly, aggressive behavior, and intellectual disability. Since 2018, PUS7 deficiency has been described in 15 patients with different pathogenic variants but similar clinical phenotypes. We describe the case of a male infant with a homozygous truncating pathogenic variant in the PUS7 gene (c.329_332delCTGA; p.Thr110Argfs*4) who, in addition to the previously mentioned features, displays self-injurious behavior, sleep disturbances and motor stereotypies.     

Possible new autosomal recessive syndrome of partial agenesis of the corpus callosum,pontine hypoplasia,focal white matter changes,hypotonia, mental retardation,and minor anomalies

We describe a brother and sister with severe developmental delay, hypotonia, partial agenesis of the corpus callosum, pontine hypoplasia, focal white matter degenerative abnormalities, macrocrania, frontal bossing, deep-set eyes, and hypertelorism. The brother also had Duane syndrome type II and an ectopic right ureter. The coexistence of these multiple physical and brain abnormalities in a brother and sister suggests a new autosomal recessive syndrome with a slowly progressive course. Am. J. Med. Genet. 73:184–188, 1997. © 1997 Wiley-Liss, Inc.     

Genetic evaluation of pervasive developmental disorders: the terminal 22q13 deletion syndrome may represent a recognizable phenotype

The evaluation of mental retardation is always a challenge to clinicians. The recognition of specific physical or behavioral characteristics can vastly improve diagnostic yield. Several genetic disorders have been identified to have certain behavioral characteristics, such as Williams syndrome, Smith-Magenis syndrome, and the velocardiofacial syndrome (VCFS). The deletion affecting the chromosome 22q in the most distal band (22q13) appears to define yet another neurobehavioral phenotype. In addition to our report, there are about 17 other cases published of this particular deletion syndrome. We describe three children who share features of developmental delay and pervasive behaviors in addition to normal to advanced growth patterns. Results of cytogenetic analysis suggest that the 3 patients share a deletion affecting the terminal 22q13 region. Two were found to have a cryptic deletion, in the third it was detected by conventional cytogenetics. The cryptic deletions were demonstrated using fluorescent in situ hybridization (FISH), where the control probe for the DiGeorge/VCFS region was deleted. While there remain gaps in our understanding of this particular deletion syndrome, we propose that patients with normal or advanced growth, significantly delayed speech, deviant development and pervasive behaviors, with minor facial dysmorphism, be screened for this deletion.     

Exome reports A de novo GNB2 variant associated with global developmental delay,intellectual disability,and dysmorphic features

Heterotrimeric G proteins are composed of α, β, and γ subunits and are involved in integrating signals between receptors and effector proteins. The 5 human Gβ proteins (encoded by GNB1, GNB2, GNB3, GNB4, and GNB5) are highly similar. Variants in GNB1 were identified as a genetic cause of developmental delay. De novo variant in GNB2 has recently been reported as a cause of sinus node dysfunction and atrioventricular block but not as a cause of developmental delay. Trio-based whole-exome sequencing was performed on an individual with global developmental delay, muscle hypotonia, multiple congenital joint contractures and dysmorphism such as brachycephalus, thick eyebrows, thin upper lip, micrognathia, prominent chin, and bilateral tapered fingers. We identified a de novo GNB2 variant c.229G>A, p.(Gly77Arg). Notably, pathogenic substitutions of the homologous Gly77 residue including an identical variant (p.Gly77Arg, p.Gly77Val, p.Gly77Ser, p.Gly77Ala) of GNB1, a paralog of GNB2, was reported in individuals with global developmental delay and hypotonia. Clinical features of our case overlap with those of GNB1 variants. Our study suggests that a GNB2 variant may be associated with syndromic global developmental delay.     

De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis

Mutations in the gene encoding fused in sarcoma (FUS) were recently identified as a novel cause of amyotrophic lateral sclerosis (ALS), emphasizing the genetic heterogeneity of ALS. We sequenced the genes encoding superoxide dismutase (SOD1), TAR DNA‐binding protein 43 (TARDBP) and FUS in 99 sporadic and 17 familial ALS patients ascertained at Mayo Clinic. We identified two novel mutations in FUS in two out of 99 (2.0%) sporadic ALS patients and established the de novo occurrence of one FUS mutation. In familial patients, we identified three (17.6%) SOD1 mutations, while FUS and TARDBP mutations were excluded. The de novo FUS mutation (g.10747A>G; IVS13‐2A>G) affects the splice‐acceptor site of FUS intron 13 and was shown to induce skipping of FUS exon 14 leading to the C‐terminal truncation of FUS (p.G466VfsX14). Subcellular localization studies showed a dramatic increase in the cytoplasmic localization of FUS and a reduction of normal nuclear expression in cells transfected with truncated compared to wild‐type FUS. We further identified a novel in‐frame insertion/deletion mutation in FUS exon 12 (p.S402_P411delinsGGGG) which is predicted to expand a conserved poly‐glycine motif. Our findings extend the mutation spectrum in FUS leading to ALS and describe the first de novo mutation in FUS. © 2010 Wiley‐Liss, Inc.