Table 2.

Summary of reportable MECP2 sequence variants detected in 4 out of 101 patients with NDDs

Patient ID	Clinical presentation	Age of testing	Sex	Variant/Zygosity	Variant classification	gnomAD	ClinVar (Classification)	Publications/HGMD	AA/nt Conser-vation	SIFT/MutationTaster/Polyphen-2
358	Iron deficiency anemia, bilateral refractive amblyopia, bilateral Myopia, gross motor delay, hypotonia, global developmental delay	2 years old	Female	NM_004992.3: c.467A > G (p.Asp156Gly)/Het	PATH	Absent	Variant ID: 143583 (VUS)	Reported in patients with Rett Syndrome (Laccone et al., 2001; Trappe et al., 2001). Functional studies suggest D156G impairs transcription suppress activity (Kudo et al., 2003). Same codon different amino acid change listed in HGMD as disease causing variant HGMD: CM011798 (DM, Rett syndrome)	Highly conserved AA	Deleterious/Disease causing/Probably damaging
18	Autism spectrum disorder, global developmental delay	1 year old	Female	NM_004992.3: c.473C > T (p.Thr158Met)/Het	PATH	Absent	Variant ID: 11811 (PATH/LIKELY PATH)	Reported in multiple females with both classic and atypical Rett syndrome and some patients don’t meet clinical criteria for Rett syndrome (Neul et al., 2008; Percy et al., 2007). Reported in RettBASE: http://mecp2.chw.edu.au/mecp2/mecp2_home.php Functional studies suggest that T158M impairs normal protein function (Kucukkal et al., 2015; Kudo et al., 2003) HGMD: CM992178 (DM, Rett syndrome)	Highly conserved AA	Deleterious/Disease causing/Probably damaging
98	Speech disturbances, language impairment, developmental delay, autism spectrum disorder, sensory sensitivities	5 years old	Female	NM_004992.3: c.824 T > C (p.Val275Ala)/Het	VUS	0.0012% in European (non-Finnish); 0.0005% in global, 0 hemi	Variant ID: 431840 (VUS)	Reported in a patient with classic Rett syndrome (Petel-Galil et al., 2006) Not in HGMD	Moderately conserved AA	Tolerated/Disease causing/Benign
215	Autism spectrum disorder, mixed receptive-expressive language disorder, global developmental delay	5 years old	Female	NM_004992.3: c.-187_-186del/Het Same with NM_001110792.1: c.-27_-26del/Het	VUS	0.0579% in European (non-Finnish), 3 Hemi; 0.0356% in global	Not reported	Reported in a female patient with mental retardation, not observed in controls (Harvey et al., 2007) HGMD: CD075460 (DM?, Mental retardation)	Nucleotides conserved	N/A

Mutation nomenclature is based on the recommendation by Human Genome Variation Society (HGVS) that nucleotide + 1 is designated the A of the ATG-translation initiation codon. AA amino acid; nt nucleotide; gnomAD genome aggregation database; HGMD human gene mutation database, PATH pathogenic; VUS variant of unknown significance. See references in supplementary data