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G9a, also known as EHMT2, is essential for embryogenesis and has specific functions in multiple developmental processes. G9a inactivation affects development of the nervous system, which is formed with contribution of descendants of progenitor cells expressing the transcription factor Isl1. However, the function of G9a in Isl1-expressing progenitors is unknown. Here, we show that G9a is required for proper development of multiple structures formed with contribution of Isl1-expressing progenitors. A Cre-dependent GFP reporter revealed that the recombinase activity of the Isl1-Cre used in this study to inactivate G9a was reduced to a subset of Isl1-expressing progenitor cells. G9a mutants reached endpoint by 7 weeks of age with cardiac hypertrophy, hydrocephalus, underdeveloped cerebellum and hind limb paralysis, modeling aspects of Dandy-Walker complex. Moreover, neuroepithelium of the lateral ventricle derived from Isl1-expressing progenitors was thinner and disorganized, potentially compromising cerebrospinal fluid dynamics in G9a mutants. Micro-computed tomography after iodine staining revealed increased volume of the heart, eye lens and brain structures in G9a mutant fetuses. Thus, altered development of descendants of the second heart field and the neural crest could contribute to multicomponent malformation like Dandy-Walker.

BACKGROUND: Dandy-Walker syndrome (DWS) is a rare congenital malformation of the central nervous system (CNS), characterized by underdevelopment or dysplasia of the cerebellar vermis, expansion of the fourth ventricle and posterior fossa cistern. The incidence is aboutapproximately 1/25000-1/35000. At present, the etiology and pathogenesis of DWS are not completely clear. It is mostly considered to be a multifactorial genetic disease that is related to both genetic factors and environmental factors. There is no large sample size analysis of the chromosomal profile of DWS up to now. This study aims to provide clinical reference for prenatal diagnosis via summarizing the clinical features and pregnancy outcomes of Dandy-Walker syndrome.
METHODS: A total of 76 cases of foetal Dandy-Walker syndrome out of 19,506 pregnant women underwent cordocentesis or amniocentesis for genetic detection. Rapid prenatal karyotyping, single nucleotide polymorphism array (SNP-array) and BACs-on-Beads™ (BoBs) were performed for prenatal genetic diagnosis. The results of ultrasonography, genetic analysis and pregnancy outcome were recorded.
RESULTS: Of the 76 cases, 19 were isolated DWS, while 57 cases were accompanied by other ultrasound-visible abnormalities. Ultrasound abnormalities of the CNS were most frequently observed, accompanied by DWS. Twenty-five out of 76 cases had chromosomal abnormalities, and the rate of chromosomal abnormalities increased in pregnant women of advanced maternal age or in combination with other ultrasound abnormalities. Of the 19 cases in the isolated DWS group, nine pregnant women chose to terminate the pregnancy, while seven cases continued the pregnancy and all infants were normal. Among the 57 pregnant women with pathological ultrasound manifestations other than foetal DWS, 44 chose to terminate the pregnancy, while 12 cases continued the pregnancy. Further follow-up revealed one newborn with postnatal neurodevelopmental delay. A female term neonate presented with very severe sensorineural deafness, and an infant died 7 days after birth with abnormal development of multiple organs.
CONCLUSIONS: Pregnant women with DWS in foetal ultrasonic examination should be offered a careful and comprehensive foetal ultrasound scan and further prenatal genetic testing including karyotype analysis and SNP-array. The prognosis of the foetus without chromosomal aberration is good in isolated DWS pregnancies but poor in nonisolated DWS pregnancies.

BACKGROUND: Dandy-Walker syndrome (DWS) is a group of brain malformations which occasionally accompanied by psychotic symptoms. The co-occurrence of DWS and epilepsy in children is quite rare.
METHODS: We reported a 14-year-old male who presented with a 8-month history of inconsistent upper limb tremor and accidental seizure. The MRI showed the typical alterations of DWS: cystic dilatation of the fourth ventricle, vermian hypoplasia, enlarged posterior fossa. He received the ventriculoperitoneal shunting (VPS) placement for hydrocephalus and had a symptom-free period for 8 days. Then he experienced a recurrence of involuntary upper limb tremor and behavior disturbance after decreasing the pressure of cerebrospinal fluid (CSF) from 150 to 130 mm Hg. After being treated with Olanzapine 10 mg/d, Clonazepam 3 mg/qn and Valproate acid (VPA) 500 mg/bid for nearly a month, his mental status and psychotic symptoms fluctuated. A search of Pub Med showed little report of hydrocephalus and DWS comorbidity with seizure and psychosis. Here we presented the whole process of a rare disease from the very beginning with all his symptoms, examinations and treatments.
CONCLUSIONS: VPS placement surgery at an earlier stage may be an effective way to avoid inevitable brain damage so as to improve the clinical outcomes for patients with DWS. Continued treatment with regard to DWS condition may include shunt placement, but it mainly focus on developmental concerns, with occupational and physical therapy along with ongoing supportive psychotherapy to improve the coping skills and quality of life.

BACKGROUND: Dandy-Walker complex and pleomorphic xanthoastrocytomas are both rare disease entities that typically manifest early in life and are associated with congenital etiological factors. Dandy-Walker complex is a cerebellar malformation associated with a series of anatomical changes. The disease onset is usually at birth or during infancy. Late onset in adulthood is uncommon. Pleomorphic xanthoastrocytoma is a rare WHO grade II astrocytic tumor affecting mainly young adults. Concomitant occurrence of Dandy-Walker complex and pleomorphic xanthoastrocytoma has not been previously reported.
METHODS: A 30-year-old woman with a previous history of unconfirmed resected lateral ventricle meningioma presented with severe headache for 1 day. Imaging examination revealed a mass in the right lateral ventricle with heterogeneous signal patterns, changes in the posterior fossa corresponding to a Dandy-Walker variant, and mild hydrocephalus.
RESULTS: Surgical complete resection of the mass was achieved. postoperative histopathological examination confirmed WHO grade II pleomorphic xanthoastrocytoma. Three years postsurgery, ventriculoperitoneal shunt was performed due to worsening of hydrocephalus. The patient has since remained symptom-free.
CONCLUSIONS: This is the first report of concomitant occurrence of Dandy-Walker complex and pleomorphic xanthoastrocytoma. The association of neurological congenital malformation with intracranial neoplasms may be multifactorial, with underlying role of genetic mutations or chromosome alterations.

Adaptor-related protein complex 1 subunit sigma 2 (AP1S2) is a subunit of AP1 that is crucial for the reformation of the synaptic vesicle. Variants in AP1S2 have been reported to cause a rare neurodevelopmental disorder, Pettigrew syndrome (PGS) (OMIM: 304,340), which is characterized by walking delay, abnormal speech, mild to profound X-linked intellectual disability (XLID), and abnormal brain, and behaviors. Here, we describe a 2-year- and 5-month-old male patient who presented with global developmental delay (GDD). Trio whole exome sequencing (WES) revealed a 5 bp duplicate in the AP1S2 gene (NM_003916.5: exon 2: c.96_100dup, p. Leu34Glnfs*8) predicted to cause early termination of translation, which was inherited from the unaffected mother. The clinical features of our patient were consistent with previous reports. This is the second case in the Chinese family and the eleventh variant found in AP1S2-related XLID. Our findings expand the AP1S2 variant spectrum in neurodevelopmental disorders and provide evidence for the application of WES in PGS diagnosis.

Methylmalonic acidemia is an organic acid metabolism disorder that usually has nonspecific clinical manifestations.
A 3-month-old female infant was admitted to the hospital for developmental retardation. Her prenatal and birth history was unremarkable. After admission, she developed dyspnea and severe anemia and was subsequently transferred to the intensive care unit. Magnetic resonance imaging of her brain showed a Dandy-Walker malformation, and metabolic screening indicated methylmalonic acidemia. Thus, she was diagnosed with methylmalonic acidemia and Dandy-Walker malformation. The patient underwent treatment including acidosis correction, blood transfusion, antibiotics, mechanical ventilation and heat preservation. Unfortunately, her condition progressively worsened and she died of metabolic crisis.
Dandy-Walker malformation may be a clinical manifestation of methylmalonic acidemia. Additionally, the co-existence of methylmalonic acidemia and Dandy-Walker malformation may be an uncharacterized syndrome which needs to be studied further.

Dandy-Walker malformation (DWM) is characterized by complete or partial agenesis of the cerebellar vermis, cyatic dilatation of the forth ventricle, and enlarged posterior fossa. However, the mechanism is still not completely understood up to now. In this study, we reported a rare case that a foetus with DWM showed partial trisomy 12p and distal 15q deletion. Karyotype analysis and chromosomal microarray analysis (CMA) were not always concordant with each other, and it is suggested that they should be performed for prenatal genetic diagnosis together. DWM is a rare central nervous system malformation, reported in 1/25-30,000 live births, characterized by complete or partial agenesis of the cerebellar vermis, cyatic dilatation of the forth ventricle, and enlarged posterior fossa (Kumar et al. 2001; Klein et al. 2003; Agrawal et al. 2016). The neurological development of children with DWM may range from normal to severely retarded, and cause variable clinical feature. Although several efforts have been made to explore its pathogenesis, however, it is still not completely understood. During the past decade, some genetic loci, microdeletion or duplication have been reported to be associated with DWM, such as 9p trisomy, partial deletions of the long arm of chromosome 13, genes ZIC1 and ZIC4 (von Kaisenberg et al. 2000; McCormack et al. 2003; Grinberg et al. 2004). In the present study, we describe a prenatal diagnosis case that a foetus with DWM on ultrasound scanning accepted genetic testing, and it revealed a microduplication of 12p13.33p11.1 and microdeletion of 15q11.2 in 750K single nucleotide polymorphism (SNP) array, while it showed 46,XX,der(8)(8pter→8q24::12p10→12qter),i(12)(p10) in karyotyping.

A boy, aged 1 month, attended the hospital due to feeding difficulty and hypotonia. He had unusual facial features (prominent forehead, hypertelorism, ptosis of the lateral canthus, thin upper lip, and low-set ears), hypotonia, and a decreased score of neonatal behavioral neurological assessment. Heart ultrasound showed atrial septal defect. Cranial MRI showed widened supratentorial ventricle, cerebral cistern, and subarachnoid space. High-throughput whole-exome sequencing of the boy detected a hemizygous mutation, c.315_320delTGAGCG, in the CCDC22 gene, which came from his mother, while such mutation was not found in his father. The unusual facies, clinical manifestations, and inheritance pattern of this boy were consistent with the manifestations of Ritscher-Schinzel syndrome reported abroad. This is a report for the first time of a case of X-linked recessive Ritscher-Schinzel syndrome caused by the hemizygous mutation c.315_320delTGAGCG in the CCDC22 gene in Chinese population.

Kabuki syndrome (KS) is a rare congenital condition with cardinal manifestations of typical facial features, developmental delays, skeletal anomalies, abnormal dermatoglyphic presentations, and mild to moderate intellectual disability. Pathogenic variants in two epigenetic modifier genes, KMT2D and KDM6A, are responsible for KS1 and KS2, respectively.
A Chinese girl had persistent neonatal hypoglycemia and Dandy-Walker variant. Whole-exome sequencing identified a novel single nucleotide deletion in KMT2D (NM_003482.3 c.12165del p.(Glu4056Serfs*10)) that caused frameshift and premature termination. The mutation was de novo. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this variant is considered pathogenic. The patient was diagnosed with KS by molecular testing.
A single novel mutation in KMT2D was identified in a KS patients with hypoglycemia and Dandy-Walker variant in the neonatal stage. A molecular test was conducted to diagnose KS at an early stage.