A NOVEL FRAMESHIFT VARIANT IN A PATIENT WITH CHD8-RELATED OVERGROWTH SYNDROME


KOCAGİL S., KEKLİKCİ A. R., KILIÇ YILDIRIM G., ÇİLİNGİR O., ERZURUMLUOĞLU GÖKALP E., DURAK ARAS B., ...More

31TH EUROPEAN MEETING ON DYSMORPHOLOGY ONLINE, Germany, 23 - 25 September 2021, vol.1, pp.34-35

  • Publication Type: Conference Paper / Summary Text
  • Volume: 1
  • Country: Germany
  • Page Numbers: pp.34-35
  • Eskisehir Osmangazi University Affiliated: Yes

Abstract

Chromodomain helicase DNA-binding protein 8 (CHD8) is an important transcriptional regulator that mostly expressed in central nervous system functioning in axonal development and neuronal migration. CHD8 gene was previously associated with autism susceptibility (# OMIM 615032) in the literature but in recent studies patients with distinct phenotype of Overgrowth/Intellectual Disability (ID) syndrome was identified. CHD8-related Overgrowth syndrome is a rare syndrome consist of mild to moderate intellectual disability, increased height and head circumference (>2SD), autism spectrum disorder, gastrointestinal problems, sleep difficulties, facial dysmorphism, seizures, neonatal hypotonia, pes planus, fifth finger clinodactyly, umbilical hernia, scoliosis and glabellar hemangioma. Facial dysmorphic findings resembled to Sotos syndrome which include, frontal bossing, down-slanting palpebral fissures, high hairline and prominent chin. Here we report a 20-month-old male patient that was referred to our outpatients’ clinics for investigation of facial dysmorphism and neuromotor developmental delay. The parents of the proband were not related and two older siblings were healthy. Prenatal screening tests and anatomical screening during pregnancy was normal. He was born at 34th week by C/S because of maternal cervical insufficiency and was admitted to the NICU for approximately one month. The patient had one seizure due to hypoglycemia in that period and had neonatal hypotonia. His birth parameters were; weight: 2800gr (90th percentile), height: 48cm (>97th percentile), head circumference: 34cm (97th percentile). Neuromotor milestones of the patient was severely delayed comparing to his peers. He gained his head control around 12 months, sit without support around 15 months, walk around 18 months and speak only with 2 words at the time of the examination. In his intracranial MRI; lateral and third ventricles were dilated, cavum septum pellucidum was detected as structural abnormalities. Ophthalmological examination of the patient revealed bilateral pale optic disc and abnormal changes of the retinal pigmentary epithelium of the fundus. In his physical examination; weight: 13kg (+0,86SD), height: 90cm (+0,99SD), head circumference: 53cm (+2,64SD) were detected. Frontal bossing, frontoparietal bolding, blonde hair, downslanted palpebral fissures, micrognathia, soft, prominent ears, dough-like skin were noted. According to the pathological findings mentioned Sotos syndrome was suspected at the patient initially. Karyotype analysis, NSD1 gene FISH analysis and NSD1 sequence analysis were performed and results were normal. Whole exome sequencing analysis was planned and at CHD8 gene, novel c.4614_4618delAAAGT variant which is classified as ‘‘Pathogenic’’ according to the ACMG classification was detected. This variant was leading to a frameshift at the 1539th position at the aminoasid chain and was generating a truncated protein. Segregation analysis was done to the asymptomatic, healthy parents and relevant variant were shown to be not present. Genetic counselling was given to the parents and inheritance risks due to the germline mosaicism were indicated. CHD8-Related Overgrowth syndrome is relatively new defined phenotype and less than 100 patients have been reported. To our knowledge our patient is the first Turkish case and also one of the youngest patients that was reported in the literature so far. He manifested the main clinical findings of the syndrome. Despite the fact that he had noticeable developmental delay it was not possible to asses the intellectual disability, behavior abnormalities because of his young age. Neonatal hypotonia, facial dysmorphism resembling Sotos syndrome and macrocephaly (>2SD) were expected features of the syndrome but normal ranged height, absence of the skeletal findings and other rare findings were distinct features.