![]() Caregivers found him to be socially interactive and very personable. At 8 years 8 months ( Figure 2g), his overall IQ was 52 (verbal IQ 64, performance IQ 47 WISC-III): he could not read or recognize numbers but could count objects, and specific weaknesses were noted in problem solving and memory (except for visual memory). By the time he reached third grade (around age 8 years), his speech was much improved and he interacted socially with his peers. Insulin-like growth factor 1 levels were normal at age 6 years 5 months. At 6 years 1 month, his verbal scores remained equivalent to age 2.5 years. A full color version of this figure is available at the Journal of Human Genetics journal online.Īt 5 years, some asymmetry of the skull was noted and X-rays revealed a bone age of 8 years. The wrist is broad, fingers are long and slender with long phalanges and very thick skin over the knuckles, and fingernails are fragile and paper-thin. The proband’s right hand shown at 30 years and 4 months ( l) is unusually large, measuring 23.5 cm. He also has numerous pigmented nevi across his chest ( i) and face ( k). His thorax is narrow and pivoted forward on his hips slightly, and slight kyphosis is apparent ( i). The main features include deep-set eyes, large low-set ears, prominent nasal root and nasal bridge with bulbous nasal tip, and retrognathia with a prominent crease between the lower lip and the chin ( j, k). Recent photographs at age 30 years and 4 months ( i– l) show dysmorphic features in adulthood. Typical features of Weaver syndrome observed in early life ( f: 7 months of age) remained apparent through childhood ( g: 8 years and h: 12 years). ( f– l) Photographs of the proband at various ages illustrate an evolving phenotype. ( e) Sanger sequencing identified a de novo c.1238C>T (p.His258Tyr) mutation in EED, exclusive to the affected proband. ( d) Pedigree of the family showing that the proband is the only affected individual. Note the rounded face, macrocephaly, retrognathia with ‘stuck-on’ chin, long and slender nose, and large low-set ears. ( a– c) Photographs of the proband at age 6 weeks ( a), 6 months ( b) and 2 and a half years ( c) show that early features were consistent with Weaver syndrome. Second proband with a constitutional mutation in EED. He could also go up and down stairs unassisted. At 26 months, he started learning sign language and at 30 months he could say 3 more words. At 22 months, he got casts for heel-cord lengthening and said his third word. Karyotype was normal (46, XY), and he was referred to Medical Genetics where his delayed motor skills, cognitive difficulties, large size and dysmorphic facies ( Figures 2a–c and f) suggested Weaver syndrome. When standing, his legs and Achilles tendons were stiff and he stood primarily on his toes physiotherapy improved his range of movement. ![]() At 17 months, he could feed himself and hold himself up he crawled a few weeks later. Developmental delay was apparent early: he could only say one word by 14 months and 2 words by 19 months. An umbilical hernia developed 1 week after birth. He had respiratory distress and mild jaundice. Apgar scores were 3 (1 min) and 4 (5 min). Birth weight was 4366 g, length 54.6 cm and head circumference 37.2 cm ( Supplementary Figures 1 and 2 and Supplementary Table 1). ![]() Ultrasound at the beginning of the third trimester identified macrosomia. The father was 36 and the mother 32 years at conception. His parents are non-consanguineous Caucasians and have younger healthy twin sons there is no family history of overgrowth. Our proband required forceps-assisted delivery after an uncomplicated term pregnancy (42 weeks by dates). The two constitutional mutations in EED associated with overgrowth are shown (current case indicated by asterisk). EED protein contains 441 amino acids (NP_003788.2) and seven WD repeats, represented here in black according to UniProt (O75530) coordinates. White (open) rectangles represent non-coding UTRs and gray rectangles represent coding exons (NM_003797.4). Exon size is represented to scale, while intronic distances are not to scale. Disruption of EED is thought to disturb this PRC2-mediated histone methyltransferase activity. This is done in a sequential manner and shuts off transcription, leading to repression of gene expression. Within PRC2, EZH2 can add up to 3 methyl groups (me) to lysine 27 on the histone 3 tail (H3K27). EED is required (along with EZH2 and SUZ12) for proper histone methyltransferase activity mediated by the SET domain of EZH2. ( a) Schematic representation of PRC2's role. Schematic of human EED and its role within the polycomb repressive complex 2 (PRC2).
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