. 2021 May 27;185(8):2417–2433. doi: 10.1002/ajmg.a.62347

TABLE 1.

Expanded cohort of TSPEAR individuals

Variant					Phenotype										Reference
Patient	Gene	Nucleotide	Amino acid	Zygosity	Hearing loss	ED	Dentition			Skin, nails, and hair				Miscellaneous
Patient	Gene	Nucleotide	Amino acid	Zygosity	Hearing loss	ED	Hypodontia	Oligodontia	Conical teeth	Nail dysplasia	Sparse hair	Hypohidrosis	Hypotrichosis	Miscellaneous
1	TSPEAR	c.533C>T	p.Pro178Leu	Hom	Yes									None	Newly reported
1	TMPRSS3	c.1204G>A	p.Gly402Arg	Hom	Yes									None	Newly reported
2	TSPEAR	c.1163T>C	p.Val388Ala	Hom	Yes									None	Newly reported
2	TMPRSS3	c.1211C>T	p.Pro404Leu	Hom	Yes									None	Newly reported
3	TSPEAR	c.1726_1728delGTCinsTT^a	p.Val576Leufs*38	Hom	Yes									None	Delmaghani et al. (2012)
4	TSPEAR	c.1566G>A	p.Pro522Pro	Het	Yes									Enlarged vestibular aqueduct, proteinuria	Sloan‐Heggen et al. (2016)
4	TSPEAR	c.1676_1677delAT	p.Tyr559Cysfs*134	Het	Yes									Enlarged vestibular aqueduct, proteinuria	Sloan‐Heggen et al. (2016)
5	TSPEAR	c.38delT	p.Leu13Argfs*38	Het	Yes	Yes			Yes	Yes	Yes			None	Newly reported
	TSPEAR	c.589C>T	p.Arg197*	Het
	GJB2	c.35delG	p.Gly12Valfs*2	Het
	GJB6	del(GJB6‐D13S1854)	NA	Het
6	TSPEAR	c.1915G>A	p.Asp639Asn	Het		Yes	Yes		Yes	Yes				Aplasia/hypoplasia of the corpus callosum, brachydactyly syndrome, cortical visual impairment, global developmental delay, nystagmus, seizures	Newly reported
6	TSPEAR	c.589C>T	p.Arg197*	Het		Yes	Yes		Yes	Yes					Newly reported
7	TSPEAR	c.1915G>A	p.Asp639Asn	Het		Yes		Yes	Yes			Yes		Abnormality of movement, intellectual disability, profound global developmental delay, self‐injurious behavior, strabismus	Newly reported
7	TSPEAR	c.1754G>T	p.Ser585Ile	Het		Yes		Yes	Yes			Yes			Newly reported
8	TSPEAR	c.589C>T	p.Arg197*	Het		Yes		Yes		Yes				Attention deficit hyperactivity disorder, abnormal heart morphology, basilar artery fenestration, recurrent otitis media, resting tremor, strabismus, tall stature	Newly reported
8	TSPEAR	c.83‐13708_1566+248del	NA	Het		Yes		Yes		Yes					Newly reported
9	TSPEAR	c.1574G>A	p.Gly525Asp	Het		Yes	Yes		Yes	Yes	Yes	Yes		Microdontia	Newly reported
9	TSPEAR	c.543‐1G>A	NA	Het		Yes	Yes		Yes	Yes	Yes	Yes		Microdontia	Newly reported
10	TSPEAR	c.942C>G	p.Tyr314*	Het		Yes			Yes	Yes	Yes	Yes	Yes	Absent meibomian glands, conductive hearing impairment, eczema, recurrent otitis media, Turner syndrome	Newly reported
10	TSPEAR	c.1469T>A	p.Leu490Gln	Het		Yes			Yes	Yes	Yes	Yes	Yes		Newly reported
11	TSPEAR	c.1726_1728delGTCinsTT	p.Val576Leufs*38	Hom		Yes	Yes				Yes		Yes	Abnormal facial shape	Peled et al. (2016)
12	TSPEAR	c.1726_1728delGTCinsTT	p.Val576Leufs*38	Het		Yes	Yes				Yes		Yes	Abnormal facial shape	Peled et al. (2016)
12	TSPEAR	c.454_457delCTGG	p.Leu152Trpfs*29	Het		Yes	Yes				Yes		Yes	Abnormal facial shape	Peled et al. (2016)
13	TSPEAR	c.1852T>A	p.Tyr618Asn	Het		Yes	Yes				Yes		Yes	Abnormal facial shape	Peled et al. (2016)
13	TSPEAR	c.1915G>A	p.Asp639Asn	Het		Yes	Yes				Yes		Yes	Abnormal facial shape	Peled et al. (2016)
14	TSPEAR	c.240T>G	p.Cys80Trp	Het		Yes			Yes					Sparse hair in childhood	Newly reported
14	TSPEAR	c.633+2C>A	NA	Het		Yes			Yes					Sparse hair in childhood	Newly reported
15	TSPEAR	c.1505delA	p.Lys502Argfs*67	Hom				Yes	Yes					Attention disorder, large anteverted ears, prognathism, speech difficulties	Newly reported
16	TSPEAR	c.1726_1728delinsTT	p.Val576Leufs*38	Het				Yes	Yes					Depressed nasal bridge, developmental delay, hypertelorism, paroxysmal dyskinesia, primary molar taurodontism, sagittal craniosynostosis, small and cupped ears	Newly reported
	TSPEAR	c.589C>T	p.Arg197*	Het
	ATP1A3	c.2767G>A	p.Asp923Asn	Het
17	TSPEAR	c.1915G>A	p.Asp639Asn	Het				Yes						Dry skin, eczema, taurodontism	Newly reported
17	TSPEAR	c.1331G>A	p.Arg444Gln	Het				Yes						Dry skin, eczema, taurodontism	Newly reported
18	TSPEAR	c.1663C>T	p.Gln555*	Het				Yes						Scoliosis	Newly reported
18	TSPEAR	c.1899dup	p.Thr634Hisfs*60	Het				Yes						Scoliosis	Newly reported
19	TSPEAR	c.1726_1728delGTCinsTT	p.Val576Leufs*38	Hom				Yes						Abnormality of the antitragus, high‐arched palate, low‐set ears, microcephaly, narrow forehead	Du et al. (2018)
20	TSPEAR	c. 1877T>C	p.Phe626Ser	Hom				Yes						None	Du et al. (2018)
21	TSPEAR	c.1528C>T	p.Arg510*	Het				Yes						None	Song et al. (2020)
21	TSPEAR	c.1330C>T	p.Arg444Trp	Het				Yes						None	Song et al. (2020)

Note: 13 newly reported TSPEAR individuals are listed alongside eight previously reported cases. The majority of these individuals segregate into three broad phenotypic categories: those who display hearing loss (#1–5), those who display ectodermal dysplasia (ED) with and without tooth agenesis (#5–21), and those who display isolated, nonsyndromic tooth agenesis (#18, 20, 21). Individual 5 presents with both hearing loss and ectodermal dysplasia without tooth agenesis, while individuals 15, 16, and 17 have nonsyndromic tooth agenesis accompanied by additional dental features such as conical teeth or taurodontism which do not satisfy diagnostic criteria for ectodermal dysplasia. Full case descriptions can be found in appendices 1 and 2.

Abbreviations: del, deletion; delins, deletion/insertion; dup, duplication; ED, ectodermal dsyplasia.

^{^a}

Variants for individual 3 were originally reported as homozygous c.1726G>T and c.1728delC variants in cis, which can alternately be reported as c.1726_1728delGTCinsTT (p.Val576Leufs*38).