Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review.

We report here the clinical diagnosis and treatment and genetic mutations of an infant with You-Hoover-Fong syndrome (YHFS). The relevant literature review was conducted. A female infant aged 17 months was admitted to Nanhai Affiliated Maternity and Children's Hospital of Guangzhou University of Chinese Medicine due to "global development delay complicated with postnatal growth retardation for more than 1 year." The infant was diagnosed with YHFS due to the onset of extremely severe mental retardation, microcephaly, abnormal hearing, severe protein-energy malnutrition, congenital cataract, cleft palate (I°), congenital atrial septal defect, brain atrophy, hydrocephalus, and brain hypoplasia. The whole exon sequencing revealed two compound heterozygous mutations, including a likely pathogenic TELO2 variant, c.2245A > T (p.K749X) from her mother and an uncertain variant, c.2299C > T (p.R767C) from her father, validated by Sanger sequencing. After bilateral cataract surgery, the infant obtained better visual acuity and showed more responses and interactions with her parents. Diagnosis and treatment of this case prompt that these TELO2 variants have not been reported, deepening the understanding of the molecular and genetic mechanism of YHFS in clinical practice.

[A case of mental retardation caused by a frameshift variant of SYNGAP1 gene].

OBJECTIVE: To explore the genetic basis for a child with mental retardation. METHODS: Whole exome sequencing was carried out for the child. Candidate variant was screened based on his clinical features and verified by Sanger sequencing. RESULTS: The child was found to harbor a c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant in the SYNGAP1 gene. Bioinformatic analysis suggested it to be pathogenic. The same variant was not detected in either parent. CONCLUSION: The c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant of the SYNGAP1 gene probably underlay the mental retardation in this child. Above finding has expanded the spectrum of SYNGAP1 gene variants and provided a basis for the diagnosis and treatment for this child.

Whole Exome Sequencing Identified Novel ARMC9 Variations in Two Cases With Joubert Syndrome.

Background: Biallelic variations in the armadillo repeat-containing 9 (ARMC9) gene were recently defined to cause Joubert syndrome (JS) type thirty. In this study, two unrelated families with probands displaying typical indications of JS were enrolled and underwent a series of clinical and genetic investigations. Methods: Routine evaluation including magnetic resonance imaging (MRI) was carried out. Whole-exome sequencing (WES) was performed on the probands to detect causative variants. Next, in silico structural and molecular dynamic (MD) analysis was conducted on the missense variant for analyzing its intramolecular impact. Meanwhile, an in vitro study with the minigene system was performed to explore the specific impact on mRNA splicing of another variant. Results: Two unrelated patients from two different families came to our hospital exhibiting typical JS presentations, such as the "molar tooth sign." Using WES, we identified that both probands carried the compound heterogeneous variants in ARMC9 (NM_025139.6), with c.1878+1G > A and c.895C > T (p.Arg299Ter) in family 1 and c.1878+1G > A and c.1027C > T (p.Arg343Cys) in family 2. These variants were inherited from their unaffected parents by Sanger sequencing, respectively, and ARMC9 c.895C > T (p.Arg299Ter) and c.1878+1G > A were novel variants. In silico analysis indicated the c.1027C > T (p.Arg343Cys) would likely affect the secondary structure of the ARMC9 protein. The minigene study demonstrated that the splice site variant c.1878+1G > A abolished the canonical donor site, resulting in an 18bp intronic retention of intron 20. Conclusion: The findings in this study expanded the mutation spectrum of ARMC9-associated JS, and we suggested that the function of ARMC9 in the pathogenesis of JS might involve the development of primary cilia, after discussing the function of the ARMC9 protein.

Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome.

PURPOSE: Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS. METHODS: Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants. RESULTS: We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants. CONCLUSION: IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.

[Scalp acupuncture for epileptiform discharges of children with cerebral palsy].

OBJECTIVE: To explore the effect of scalp acupuncture for children with cerebral palsy whose video-electroencephalogram(VEEG) showed epileptiform discharges. METHODS: A total of 184 children with cerebral palsy whose VEEG showed epileptiform discharges or those combined with epilepsy were randomly assigned into a combination group (99 cases) and a rehabilitation group (85 cases). All the cases were treated with the original antiepileptic drugs. The conventional physical training and massage were applied in the rehabilitation group for 3 courses with 20 d at the interval, once a day, 5 times a week and 15 times as one course. Based on the treatment as the rehabilitation group, scalp acupuncture was used in the combination group for 3 courses with 15 d at the interval, once the other day and 10 times as one course. Shenting (GV 24), Benshen (GB 13), Sishencong (EX-HN 1) were selected as the main acupoints, combined with motor zone, foot motor-sensory area, balance zone,and temple-three-needle etc. Clinical onset and VEEG results were observed before and after treatment. RESULTS: After treatment in the combination group, 27 cases improved; 47 cases had no effect; 25 cases aggravated. While in the rehabilitation group, 11 cases improved; 46 cases had no effect; 28 cases aggravated. There was no statistically significance between the two groups (P>0.05). As for the cases with epilepsy onset in the combination group, 8 cases improved; 4 cases had no effect; 4 cases aggravated. In the rehabilitation group, 4 cases had no effect; 7 cases aggravated. The result in the combination group was better than that in the rehabilitation group (P<0.05). As for the cases with epileptiform discharges in the combination group, 19 cases improved; 43 cases had no effect; 21 cases aggravated. In the rehabilitation group, 11 cases improved; 42 cases had no effect; 21 cases aggravated. There was no significance between the two groups (P>0.05). CONCLUSIONS: Scalp acupuncture therapy does not increase the risk of onset or epileptiform discharges in the children with cerebral palsy combined with epilepsy or epileptiform discharges. Scalp acupuncture combined with rehabilitation is better than simple rehabilitation for thosewith cerebral palsy and epilepsy onset.