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The major goals of the study on non-syndromic hearing loss (NSHL) at The Rockefeller University are: to localize novel NSHL gene(s); refine the genetic region for known NSHL loci; and isolate NSHL genes. This study offers the basic research which will aid in understanding the function of genes controlling the mechanism of hearing. This knowledge in turn should facilitate the development of intervention strategies to prevent and treat hearing loss.

Hearing impairment, which ranges in severity from modest difficulty with speech comprehension through profound hearing loss, affects 28 million Americans. Approximately one in every thousand children is born with a significant hearing impairment. An additional 1/1,000 children become severely hearing impaired before adulthood (Morton 1991; Reardon 1992). More than 60 percent of the cases of profound early-onset deafness are caused by genetic factors, which in most cases are due to single gene mutations (Marazita et al. 1993). About 75 percent of individuals with genetically determined deafness have no other clinical features, the other 25% have identifiable syndromes (Morton 1991; Reardon 1992; Marazita et al. 1993). It is estimated that approximately 75% of cases display autosomal recessive inheritance, 15% of cases are autosomal dominant and 2-3% cases are X-linked (Fraser 1976). NSHL can also be due to mitochondrial inheritance (Prezant et al. 1993).

It is estimated that for NSRHL (autosomal recessive NSHL) there are between 30-100 genes (Chung et al. 1959, Morton 1991). Over 60 NSHL loci have been localized (33 autosomal dominant loci [DFNA], 29 autosomal recessive loci [DFNB] and 5 X-linked loci [DFN]). Twenty one genes have been identified.

Gene	OMIM	Encoded Product	Loci	Position	Reference
ACTG1	102560		DFNA20/26	17q25.3	Zhu et al. 2003
CDH23	605516	Cadherin-23(otocadherin)	DFNB12	10q22.1	Bork et al. 2001
CLDN14	605608	Claudin-14	DFNB29	21q22.13	Wilcox et al. 2001
COCH	601369	COCH	DFNA9	14q12	Robertson et al. 1998
COL11A2	120290	Collagen, type XI	DFNA13	6p21.32	Brown et al. 1997 McGuirt et al. 1999
CRYM	123740	CRYSTALLIN		16p13.11-p12.3	Abe et al., 2003
DFNA5	600994	DFNA5	DFNA5	7p15.3	Van Laer et al. 1998
DIAPH1	602121	Diaphanous 1	DFNA1	5q31.3	Lynch et al. 1997
EYA4	601316	EYA (Eye Absent - transcriptonal act.)	DFNA10	6q23.2	Wayne el at. 2001
GJA1	121014	connexin 43		6q22.31	Liu et al. 2001
GJB2 (Cx26)	121011	Connexin 26	DFNA3 DFNB1	13q12.11	Kelsell et al. 1997
GJB3 (Cx31)	603324	Connexin 31	DFNA2	1p34.3	Xia et al. 1998
GJB6 (Cx30)	604418	Connexin 30	DFNA3	13q12.11	Grifa et al. 1999
HARMONIN	605242	HARMONIN	DFNB18	11p15.1	Ahmed et al, 2002
KCNQ4	603537	KCNQ4	DFNA2	1p34.2	Kubisch et al. 1999
MYH9	160775	Myosin-9	DFNA17	22q12.3	Lawani et al. 2000
MYO1A	601478	Myosin IA	DFNA48	12q13.3	Donaudy et al., 2003
MYO3A	606808	Myosin IIIA	DFNB30	10q11.1	Walsh et al. 2002
MYO6	600970	Myosin-VI	DFNA22 DFNB37	6q14.1	Melchionda et al. 2001 Ahmed et al, 2003
MYO7A	276903	Myosin VIIA	DFNA11 DFNB2	11q13.5	Liu et al. 1997a Liu et al. 1997b Weil et al. 1997
MYO15	602666	Myosin XV	DFNB3	17p11.2	Wang et al. 1998
OTOA	607038	otoancorin	DFNB22	16p12.2	Zwaenepoel et al. 2002
OTOF	603681	Otoferlin	DFNB9	2p23.3	Yasunaga et al. 1999
PCDH15	605514	Protocadherin 15	DFNB23	10q21-q22	Ahmed et al, 2003
PDS/SLC26A4	274600	Pendrin	DFNB4	7q31.1	Li et al. 1998 Cremers et al. 1998 Phelps et al. 1998 Tsukamoto et al. 2003
POU4F3	602460	POU4F3	DFNA15	5q32	Vahava et al. 1998
POU3F4	300039	POU3F4	DFN3	Xq21	Bitner et al. 1995 Hagiwara et al. 1998 Oh et al. 2003
SLC26A5	604943	Prestin		7q22.1	Zheng et al. 2000 Oliver et al. 2001 Liu et al, 2003
STRC	606440	Stereocilin	DFNB16	15q15	Verpy et al. 2001
TECTA	602574	Alpha-Tectorin	DFNA8/12 DFNB21	11q23.3	Verhoeven et al. 1998 Mustapha et al. 1999
TFCP2L3		Unknown	DFNB28	8q22	Peters et al. 2000
TMC1	606706	TMC1	DFNA36 DFNB7/B11	9q21.13	Kurima et al. 2002 Vreugde et al. 2002
TMIE	607237	TMIE (transmembrane inner ear expressed gene)	DFNB6 DFNA36	3p21	Mitchem et al. 2000 Naz et al. 2002
TMPRSS3	605511	Transmembrane protease, serine 3	DRNB8/10	21q22	Scott et al. 2001
WFS1	606201	Wolframin	DFNA6/14	4p16.1	Bespalova et al. 2001
WHRN	607928	CASK	DFNB31	9q32	Mburu et al. 2003 Yap et al. 2003

Table 2 and Table 3 provides genetic and clinical information for NSDHL and NSRHL, respectively. In Tables 2 and 3 the columns are as follows: 1) locus name (hot link to OMIM entry); 2) chromosomal location; 3) the gene; 4) origin of families which have shown linkage to a particular locus; 5) age of onset; 6) evolution of hearing loss; 7) affected frequencies; and 8) most important reference(s).

Table 2: Identified Autosomal Dominant Loci for Non-sydromic Hearing Loss. Table 2

Locus (OMIM #)	Location	Gene	Origin of Families	Onset	Evolution	Affected Frequencies	Most Important Reference(s)
DFNA1 (124900)	5q31	DIAPH1	Costa Rica	5-20 yrs	Progressive starting in the low frequencies	All	Leon et al. 1992; Lynch et al. 1997
DFNA2 (600101)	1p34	GJB3 KCNQ4	Indonesia, USA, Belgium, Netherlands	Decade 1-3	Progressive to severe hearing loss	High, progressive to low	Coucke et al. 1994; Xia et al. 1999; Kubisch et al. 1999
DFNA3 (601544)	13q12	GJB2 GJB6	France	Prelingual	Stable or progressive, moderate to severe hearing loss	All, greatest in high frequencies	Chaib et al. 1994; Kelsell et al. 1997; Denoyelle et al. 1998
DFNA4 (600652)	19q13	unknown	USA	Decade 3-4	Slow or rapid progression to severe hearing loss	High, progressive to low	Chen et al. 1995
DFNA5 (600994)	7p15	DFNA5	Netherlands	Decade 1-3	Progressive to severe hearing loss	High, progressive to low	Van Camp et al. 1995; 1998
DFNA6 (600965)	4p16.1	WFS1	USA (Irish descent), Netherlands	Decade 1-2	Slowly Progressive	Low, Progressive to high	Lesperance et al. 1995 Bespalova et al. 2001 Young et al. 2001
DFNA7 (601412)	1q21-q23	unknown	Norway	Decade 1-2	Progressive	High, Progressive to low	Fagerheim et al. 1996
DFNA8/12 (601543/ 601842)	11q22-24	TECTA	Austria, Belgium	Prelingual	Moderate to profound, non-progressive Mild to moderately-severe hearing loss	All	Verhoeven et al. 1998
DFNA9 (601369)	14q12-q13	COCH	USA, Austria, Belgium, Nertherlands	~20 or ~40 yrs	Progressive to profound hearing loss, starting in the high frequencies	All	Manolis et al. 1996; Robertson et al. 1998; Fransen E et al. 1999; Kamarinos M et al. 2001
DFNA10 (601316)	6q22-q23	EYA4	USA, Belgium	Decade 2-4	Postlingual, slow or rapid progression to severe hearing loss	All	Wayne et al. 2001
DFNA11 (601317)	11q12.3-q21	MYO7A	Japan	Postlingual, 1st Decade	Moderate, progressive	All	Tamagawa et al. 1996 Liu et al. 1997
DFNA13 (601868)	6p21	COL11A2	USA, Dutch	Decade 2-4	Nonprogressive, predominantly affects middle frequencies	All	Brown et al. 1997 McGuirt et al. 1999
DFNA14 (605957)	4p16.1	WFS1	Dutch, USA (Irish descent)	Decades 1-2	Stops short of profound deafness	low and mid frequencies	Van Camp et al. 1999 Bespalova et al. 2001
DFNA15 (602459)	5q31	POU4F3	Israel	18-30 yrs of age	Progreessive hearing loss, moderate to severe by age 50	All	Vahava et al. 1998
DFNA16 (603964)	2q24	unknown	Japan		Progressive hearing loss, Mild to Moderate	Affecting mainly the high frequencies	Fukushima et al. 1999
DFNA17 (603622)	22q	MYH9	USA	1st decade of life	Progressive to moderate to severe by the 3rd decade of life		Lalwani et al. 1999 Lalwani et al. 2000
DFNA18(606012)	3q22	unknown	Germany	1st decade of life	severe progressive	All	Bonsch et al. 2001
DFNA19	10 pericentromeric	unknown					Green et al. 1998
DFNA20/26 (604717)	17q25	ACTG1	USA	13-25 yrs of age	Progressive, first evident at 6-8 KHz	All	Morell et al. 2000 Yang et al. 2000 Zhu et al, 2003
DFNA22 (606346)	6q13	MYO6	Italy	childhood	progressive, postlingual		Melchionda et al. 2001
DFNA23 (605192)	14q21-q22	unknown	Switzerland (Swiss German)	prelingual	Stable or progressive	Low, mid and high frequencies, moderate to profound	Salam et al. 2000
DFNA24 (606282)	4q35-qter	unknown	Switzerland (Swiss German)	prelingual	nonprogressive	Affecting mainly the mid to high frequencies	Häfner et al. 2000
DFNA25 (605583)	12q21-24	unknown	Czech Republic	1st two decades of life	progressive	high frequencies	Greene et al. 2001
DFNA27	4q12	unknown		11-29 yrs. of age	Progreessive hearing loss, moderate to severe by age 40		Fridell et al. 1999
DFNA28	8q22	TFCP2L3	USA	postlingual	Progreessive hearing loss, moderate to severe by age 40.	high or mid-frequencies	Anderson et al. 1999 Peters et al, 2002
DFNA30 (606451)	15q26	unknown	Italy	end of 1st decade of life	Rapid progression to moderate to severe until the 4th decade of life	mid and high frequencies	Mangino et al. 2001
DFNA32	11p15	unknown	USA		Progressive hearing loss		Li et al. 2000
DFNA34	1q44	unknown		3rd or 4th decade	Slow progressive rate		Kurima et al. 2000
DFNA36 (606705)	9q13-q21	TMC1	USA	1st decade	Rapidly progresses to profound by early adulthood		Kurima et al. 2002
DFNA37	1p21	unknown	USA	prelingual	High progressing to low		Talebizadeh et al. 2000
DFNA39 (605594)	4q21.3	DSPP	Chinese	3rd and 5th decade	Progressive, moderate to severe	progressive high frequency and low	Xiao et al. 2001
DFNA41	12q24-qter	unknown	Chinese	after their teens	Progressive, from moderate to profound loss	All	Liu et al. 2001
DFNA43	2q12	unknown	Italian	second decade of life	Subsequent gradual progression from moderate to profound loss	All	E. Flex et al. 2002
DFNA44 (607453)	3q28-29	unknown	Spanish		Bilateral and progressive		Modamio-Hoybjor et al. 2003
DFNA47	9p21-22	unknown	Italian	after their teens	Progressive, subsequent gradual progression to a moderate-severe loss		D'Adamo et al. 2003
DFNA48	12q13-q14	unknown	Italian				D'Adamo et al. 2003

Locus (OMIM #)	Location	Gene	Origin of Families	Onset	Evolution	Affected Frequencies	Most Important Reference(s)
DFNB1 (220290)	13q12	GJB2	Tunisia, Israel (Bedouin), Pakistan, Australian	Usually prelingual	Stable, severe-to-profound loss	All	Guilford et al. 1994a Kelsell et al. 1997
DFNB2 (600060)	11q13.5	MYO7A	Tunisia	Birth-16yrs	Stable, profound	All	Guilford et al. 1994b Liu et al. 1997 Weil et al. 1997
DFNB3 (600316)	17p11.2-q12	MYO15	Bali, India	Congenital	Stable, profound	All	Friedman et al. 1995 Wang et al. 1998
DFNB4 (600791)	7q31	PDS SLC26A4	Israel (Druze)	Congenital	Stable, severe-to-profound	All	Baldwin et al. 1995 Li et al. 1998
DFNB5 (600792)	14q12	unknown	India	Congenital	Stable, Severe-to-profound loss	All	Fukishima et al. 1995a
DFNB6 (600971)	3p14-p21	TMIE	India	Congenital	Stable, Severe-to-profound loss	All	Fukishima et al. 1995b Naz et al. 2002
DFNB7/11 (600974)	9q13-q21	TMC1	India, Israel (Bedouin)	Congenital	Stable, Severe-to-profound loss/ Profound	All	Jain et al. 1995 Scott et al.1996 Kurima et al. 2002
DFNB8/10 (601072)	21q22	TMPRSS3	Pakistan, Israel (Palestinian)	10-12yrs/ Congenital	Progressive to severe hearing loss/ Stable, severe loss	All	Veske et al. 1996 Scott et al. 2001
DFNB9 (601071)	2p22-p23	OTOF	Lebanon, Turkey	Congenital	Stable, profound	All	Chaib et al. 1996a Yasunaga et al. 1999
DFNB12 (601386)	10q21-22	CDH23	Syrian	Congenital	Stable, profound	All	Chaib et al. 1996b Bork et al. 2001
DFNB13 (603098)	7q34-36	unknown	Lebanon	Prelingual	Severe progressive		Mustapha et al. 1998
DFNB14 (603678)	7q31	unknown	Lebanon	Prelingual	Profound		Mustapha et al. 1998
DFNB15 (601869)	3q21-q25 19p13	unknown	India	Prelingual	Stable	All	Chen et al. 1997
DFNB16 (603720)	15q15 15q21-22	STRC	Pakistan, Palistine, Syria, France	3-5 years of age	Non-progressive, moderate mid frequencies and severe high frequencies	All	Campbell et al. 1997 Verpy et al. 2001
DFNB17 (603010)	7q31	unknown	India, Middle Eastern Druze	Prelingual	Profound	All	Greinwald et al. 1998
DFNB18 (602092)	11p14-15.1	USH1C	India		Profound		Jain et al. 1998 Ahmed et al, Human Genetics online
DFNB19	18p11	unknown		Congenital	Profound	All	Green et al. 1998
DFNB20 (604060)	11q25-qter	unknown	Pakistan	3 months ~ 1 year of age	Profound	All	Moynihan et al. 1999
DFNB21 (603629)	11q	TECTA	Lebanon	Prelingual	Profound	Moderately severe ~ all	Mustapha et al. 1999
DFNB22 (607038)	16p12.2	OTOA	Palestine		Profound		Zwaenepoel et al. 2002
DFNB23	10p11.2-q21	PCDH15					Ahmed et al, 2003
DFNB24	11q23	unknown					Richard Smith, unpublished
DFNB25	4p15.3-q12	unknown					Richard Smith, unpublished
DFNB26 (605428)	4q31	unknown	Pakistan	Prelingual	Profound	All	Riazuddin et al. 2000
DFNB27 (605818)	2q23-q31	unknown	United Arab Emirate				Pulleyn et al. 2000
DFNB28	22q13	unknown	Palestine	Prelingual	Profound		Walsh et al, 2000
DFNB29 (605608)	21q22	CLDN14