TABLE 1.

Demographics, clinical, behavior/cognition, and molecular genetics of individuals with rare FMR1 gene mutations

Clinical category	De Boulle et al. (1993)	Lugenbeel et al. (1995)	lugenbeel et al. (1995)	Wang et al. (1997)	Gronskov et al. (2011)	Handt et al. (2014)	Handt et al. (2014)	Handt et al. (2014)	Myrick et al. (2014)	Wright et al. (2015)	Myrick, Hashimoto et al. (2015)a	Okray et al. (2015)	Suhl et al. (2015)	Grozeva et al. (2015)	Hu et al. (2016)	Quartier et al. (2017)	Quartier et al. (2017)	Quartier et al. (2017)	Quartier et al. (2017)	Quartier et al. (2017)	Present case
Demographics
Age (y)	27	3	~30	N/a	35	4	11	11	16	N/a	12	36	10	N/a	N/a	50	48	47	10	20	10
Ethnicity	Caucasian	Caucasian	Caucasian	N/a	Caucasian	Caucasian	Caucasian	Caucasian	Caucasian	N/a	Caucasian	Caucasian	Black	N/a	N/a	Caucasian	Caucasian	Caucasian	Caucasian	Caucasian	Caucasian
Gender	Male	Male	Male	N/a	Male	Male	Male	Male	Male	N/a	Male	Male	Male	N/a	N/a	Male	Male	Male	Male	Male	Male
Current height	1.85m (90th centile)	N/a	N/a	Male	N/a	98th centile	WNL	97th centile	1.72m (45th centile	N/a	25th centile	WNL	1.6m (75th centile)	N/a	N/a	N/a	N/a	N/a	75th centile (+1 SD)	1.76m (95th centile)	1.36m (35th centile)
Current weight	65kg (50th centile)	N/a	N/a	N/a	N/a	98th centile	WNL	97th centile	52.3kg (17th centile)	N/a	25th centile	WNL	39.9kg (60th centile)	N/a	N/a	N/a	N/a	N/a	(−0.5 SD)	59.2kg (50th centile)	25.7kg (10th centile)
Clinical features
Enlarged testicles	Yes (>100 ml)	No	Yes (75 mL)	N/a	Yes	N/a	N/a	N/a	Yes	N/a	No	Yes	N/a	N/a	N/a	Yes	Yes	Yes	No	No	No (3–4 ml)
Dysmorphic features	Yes	Yes	Yes	N/a	Yes	N/a	N/a	N/a	Yes	N/a	No	Yes	Yes	N/a	N/a	Yes	Yes	Yes	Yes	Yes	Yes
Epicanthal folds	No	Yes	N/a	Yes	no	N/a	N/a	N/a	N/a	N/a	No	N/a	No	N/a	N/a	No	No	No	N/a	No	No
Elongated face	Yes; asymmetric	Yes	Yes	N/a	Yes	N/a	N/a	N/a	Yes	N/a	No	N/a	Yes	N/a	N/a	Yes	Yes	Yes	Yes	Yes	Yes
Prognathism	Yes	N/a	Yes	Yes	Yes	N/a	N/a	N/a	N/a	N/a	No	Yes	Yes	N/a	N/a	No	Yes	Yes	Yes	Yes	no
Broad high forehead	Yes	Yes	Yes	Yes	Yes	N/a	N/a	N/a	Yes	N/a	No	Yes	N/a	N/a	N/a	Yes	No	Yes	Yes	Yes	Yes
Prominent ears	Yes	Yes	Yes	Yes	Yes	N/a	N/a	N/a	Yes	N/a	Yes	Yes	Yes	N/a	N/a	Yes	Yes	Yes	Yes	no	Yes
Hypermobility/hyper-extensible joints	N/a	Yes	Yes	Yes	Yes	N/a	N/a	N/a	Yes	N/a	N/a	Yes	Yes	N/a	N/a	Yes	Yes	Yes	Yes	Yes	Yes
Hypotonia	N/a	N/a	N/a	N/a	Yes	N/a	N/a	N/a	N/a	N/a	N/a	N/a	N/a	N/a	N/a	N/a	N/a	N/a	N/a	N/a	Yes
Seizures	Focal	N/a	N/a	N/a	Tonic-clonic	N/a	N/a	N/a	N/a	N/a	Partial	No	No	N/a	N/a	Yes	No	No	N/a	N/a	Partial complex
Behavioral/cognitive
Autism	N/a	Yes	Yes	N/a	Tactile defensive, limitedinterests	N/a	N/a	N/a	Yes	N/a	No	Yes	Yes	N/a	N/a	Yes	Yes	Yes	Yes	Yes	Yes
Verbal ability	No	Perseveration and cluttering of phrases	Rapid speech with classical cluttering	N/a	Few words, out of context	Impaired	N/a	N/a	Yes	N/a	Yes, complete sentences	N/a	Yes	N/a	N/a	NO	Yes	No	N/a	N/a	no
ADHD	N/a	Yes	N/a	N/a	N/a	Yes	N/a	Yes	N/a	N/a	N/a	N/a	Yes	N/a	N/a	Yes	Yes	Yes	No	Yes	Yes
Developmental delay	Yes	Yes	Yes	Yes	Yes	Mild/moderate	Yes	Yes	Yes	N/a	Yes	N/a	Yes	N/a	N/a	Yes	Yes	Yes	Yes	Yes	Yes
Language impairment	Yes	Yes	N/a	N/a	Yes	Yes	Yes	N/a	Yes	N/a	Yes	Yes	Yes	N/a	N/a	Yes	Yes	Yes	No	Yes	Yes
Cognitive impairment/Intelligence quotient	IQ<20	N/a	N/a	Yes	Yes	Psychomotor delay	Learning impairment	Learning disability	N/a	N/a	IQ=42	IQ=41	IQ=47	N/a	N/a	Yes	Yes	Yes	Yes	Yes	IQ=42
Other
	Hepatomegaly, glycogenesis, growth retardation, spastic paraparesis, increased DTRs, flat feet, knee anomaly	Reduced balance	Toe walking, hand flapping, obsessions		Myoclonus		Normal head size, right pre-auricular tag	Agitation, outbursts, macrocephaly, urinary incontinence			Mild macrocephaly	Periodic aggressive outbursts	Birthmarks			Marfanoid habitus, gynecomastia, affected brothers	Marfanoid habitus, affected brothers	Marfanoid habitus, affected brothers	Fifth digit clinodactyly, short toes, shawl scrotum	Third and fifth digit clinodactyly	Strabismus, mitral valve prolapse, wide mouth, hirsutism
Molecular genetics
Mutation type	Hissense	1-bp deletion-frameshift	2-bp change	Intron 10 C>T	Nonsense	Missense	Missense	Missense	Missense	Missense	Missense	Nonsense	3’UTR	Missense	Missense	Nonsense	Nonsense	Nonsense	frameshift	Nonsense	Missense
Genomic location	c.11OOT>A	c.373delA	g.23714GG-TA	IVS10+14 (C>T)	c.80C>A	c.1444G>A	c.1601G>A	c.1601G>A	c.797G>A	c.377T>C	c.413G>A	1457insG	c.*746T>C	c.677G>A	c.1618G>A	r.1737_1738ins1737+1_?	r.1737_1738ins1737+1_?	r.1737_1738ins1737+1_?	c.990+1G>A	c.420-8A>G	c.413G>A
Amino acid protein position	p.11e367Asn	p.Thr126Leu			p.Ser27X	p.Gly482Ser	p.Arg534His	p.Arg534His	p.Gly266Glu	p.Phe126Ser	p.Arg138Gln	frameshift, stop codon		p.Arg226Lys	p.Gly540Glu	p.lle580fs*9	p.lle580fs*9	p.lle580fs*9	p.Lys295Asnfs*11	p.Met140llefs*3	p.Arg138Gln
Exon	Exon 11	Exon 5	Intron/Exon 2 boundary	Intron/exon 10 boundary exon 10 skipped	Exon 2	Exon 14	Exon 15	Exon 15	Exon 8	Exon 5	Exon 5	Exon 15		Exon 8	Exon 15	Exon 17	Exon 17	Exon 17	Exon 10 skipped (r.881_990del)	Exon 6	Exon 5
Classification	VUS	LP	IP	LP	P	VUS	VUS	VUS	VUS	VUS	LP	P	VUS	VUS	VUS	LP	LP	LP	LP	LP	LP
Protein domain	KH2	NLS	Agenet1	KH2	Agenet1		RGG	RGG	KH1	NIS	NLS	RGG		KH1	R6G				KH2	NES	NIS
Positive family history	N/a	N/a	Yes; mother	N/a	Yes; mother	N/a	Yes; mother, sister	Yes; mother	N/a	N/a	Yes; mother	N/a	Yes; mother, half brother	N/a	N/a	Yes; mother, two brothers	Yes; mother, two brothers	Yes; mother, two brothers	No, de novo	Yes; heterozygous mother	Yes; mother, sister

DTRs, deep tendon reflexes; LP, likely pathogenic; N/a, not available; P, pathogenic; VUS, variant of uncertain significance; WNL, within normal limits.

^aMolecular genetic findings reported by Collins et al. (2010).