Study Goals

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. 

Background Information on Non-Syndromic Hearing Loss (updated 6/13/02)

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 (32 autosomal dominant loci [DFNA], 28 autosomal recessive loci [DFNB] and 5 X-linked loci [DFN]). Twenty-nine genes have been identified. 

Table 1: Identified Genes for Non-sydromic Hearing Loss. Table 1

Gene	OMIM	Encoded Product	Loci	Reference
CDH23	605516	Cadherin-23(otocadherin)	DFNB12	Bork et al. 2001
CLDN14	605608	Claudin-14	DFNB29	Wilcox et al. 2001
COCH	601369	COCH	DFNA9	Robertson et al. 1998
COL11A2	120290	Collagen, type XI	DFNA13	Brown et al. 1997 McGuirt et al. 1999
DFNA5	600994	DFNA5	DFNA5	Van Laer et al. 1998
DIAPH1	602121	Diaphanous 1	DFNA1	Lynch et al. 1997
DSPP	125485	Dentin sialophosphoprotein	DFNA39	Xiao et al, 2001
EYA4	601316	EYA (Eye Absent - transcriptonal act.)	DFNA10	Wayne el at. 2001
GJA1	121014	connexin 43		Liu et al, 2001
GJB2 (Cx26)	121011	Connexin 26	DFNA3 DFNB1	Kelsell et al. 1997
GJB3 (Cx31)	603324	Connexin 31	DFNA2	Xia et al. 1998
GJB6 (Cx30)	604418	Connexin 30	DFNA3	Grifa et al. 1999
HARMONIN	605242	HARMONIN	DFNB18	Ahmed et al, 2002
KCNQ4	603537	KCNQ4	DFNA2	Kubisch et al. 1999
MYH9	160775	Myosin-9	DFNA17	Lawani et al, 2000
MYO3A	606808	MYOSIN IIIA	DFNB30	Walsh et al. 2002
MYO6	600970	Myosin-VI	DFNA22	Melchionda et al, 2001
MYO7A	276903	Myosin VIIA	DFNA11 DFNB2	Liu et al, 1997a Liu et al,, 1997b Weil et al, 1997
MYO15	602666	Myosin XV	DFNB3	Wang et al. 1998
OTOA		otoancorin	DFNB22	Zwaenepoel et al, 2002
OTOF	603681	Otoferlin	DFNB9	Yasunaga et al. 1999
PDS/SLC26A4	274600	Pendrin	DFNB4	Li et al. 1998
POU4F3	602460	POU4F3	DFNA15	Vahava et al. 1998
STRC	606440	stereocilin	DFNB16	Verpy et al. 2001
TECTA	602574	Alpha-Tectorin	DFNA8/12 DFNB21	Verhoeven et al. 1998 Mustapha et al. 1999
TMC1	606706	TMC1	DFNA36 DFNB7/B11	Kurima et al, 2002 Vreugde et al, 2002
TMPRSS3	605511	Transmembrane protease, serine 3	DRNB8/10	Scott et al. 2001
WFS1	606201	Wolframin	DFNA6/DFNA14	Bespalova et al. 2001

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	6-20 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 Kubisch et al. 1999
DFNA3 (601544)	13q12	GJB2  GJB6	France	Prelingual	Stable or progressive, moderate to severe hearing loss	All, greatest in high frequencies	Chiab et al. 1994 Kelsell et al. 1997 Denoyelle et al. 1998
DFNA4 (600652)	19q13		USA	Decades 3-4	Slow or rapid progression to severe hearing loss	High, progressive to low	Chen et al. 1995
DFNA5 (600994)	7p15	DFNA5	Netherlands	Decades 1-2	Progressive to severe hearing loss	High, progressive to low	Van Camp et al. 1995; 1998
DFNA6 (600965)	4p16.1	WFS1	USA (Irish descent), Netherlands	Decades 1-2	Slowly Progressive	Low, Progressive to high	Lesperance et al. 1995 Bespalova et al. 2001
DFNA7 (601412)	1q21-q23		Norway	Decades 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	Not disclosed	~20 yrs	Progressive, starting in the high frequencies	High frequencies	Manolis et al. 1996
DFNA10 (601316)	6q22-q23	EYA4	USA Belgian	Decades 2-4	Postlingual, slow or rapid progression to severe hearing loss	All	O'Neill et al. 1996 Wayne et al. 2001
DFNA11 (601317)	11q12.3-q21	MYO7A	Japan	Decade 1	moderate, progressive	All	Tamagawa et al. 1996
DFNA13 (601868)	6p21	COL11A2	USA	Decade 2-4	Moderate-severe progressive hearing loss starting in mid-frequencies	All	Brown et al. 1997
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		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	3q22		Germany				Boensch et al. 1998
DFNA19	10 pericentromeric						Green et al. 1998
DFNA20 (604717)	17q25		USA	13-25 yrs  of age	Progressive, first evident at 6-8 KHz	All	Morell et al. 2000
DFNA22(606346)	6q13	MYO6	Italy	childhood	progressive, postlingual		Melchionda et al. 2001
DFNA23 605192	14q21-q22		Switzerland (Swiss German)	prelingual	Stable or progressive	Low, mid and high frequencies, moderate to profound	Salam et al. 2000
DFNA24	4q35-qter		Switzerland (Swiss German)	prelingual	nonprogressive	Affecting mainly the mid to high frequencies	Häfner et al. 2000
DFNA25 605583	12q21-24		Czech Republic	1st two decades of  life	progressive	high frequencies	Greene et al. 2001
DFNA26	17q25						Yang et al. 2000
DFNA27	4q12			11-29 yrs. of age	Progreessive hearing loss, moderate to severe by age 40		Fridell et al. 1999
DFNA28	8q22		USA	postlingual	Progreessive hearing loss, moderate to severe by age 40.	high or mid-frequencies	Anderson et al. 1999
DFNA30	15q26		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. 1999
DFNA32	11p15		USA		Progressive   hearing loss		Li et al, 2000
DFNA34	1q44			1st decade	Rapidly    progresses to profound by early   adulthood		Kurima et al, 2000
DFNA36	9q12-q21			3rd or 4th decade	Slow progressive rate		Kurima et al, 2000 Kurima et al, 2002
DFNA37	1p21		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

Table 3: Identified Autosomal Recessive Loci for Non-sydromic Hearing Loss.Table 3
 

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
DFNB2 (600060)	11q13.5	MYO7A	Tunisia	Birth-16yrs	Stable, profound	All	Guilford et al. 1994b
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	Li et al. 1998
DFNB5 (600792)	14q12		India	Congenital	Stable, Severe-to-profound loss	All	Fukishima et al. 1995a
DFNB6 (600971)	3p14-p21		India	Congenital	Stable, Severe-to-profound loss	All	Fukishima et al. 1995b
DFNB7/11 (600974)	9q13-q21		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		Lebanon	Prelingual	Severe progressive		Mustapha et al. 1998
DFNB14 (603678)	7q31		Lebanon	Prelingual	Profound		Mustapha et al. 1998
DFNB15 (601869)	3q21-q25  19p13		India	Prelingual	Stable	All	Chen et al. 1997
DFNB16 (603720)	15q15 15q21-22	STRC	Pakistan, Palistine, Syria, France	3-5 years of age	Profound	High frequencies	Campbell et al. 1997 Verpy et al. 2001
DFNB17 (603010)	7q31		India				Greinwald et al. 1998
DFNB18 (602092)	11p14-15.1		India		Profound		Jain et al. 1998 Ahmed et al, Human Genetics online
DFNB19	18p11			Congenital	Profound	All	Green et al. 1998
DFNB20 (604060)	11q25-qter		Pakistan				Moynihan et al. 1999
DFNB21 (603629)	11q	TECTA	Lebanon	Prelingual	Profound		Mustapha et al. 1999
DFNB22	16p12.2	OTOA					Zwaenepoel et al., 2002
DFNB23	10p11.2-q21						Richard Smith, unpublished
DFNB24	11q23						Richard Smith, unpublished
DFNB25	4p15.3-q12						Richard Smith, unpublished
DFNB26 (605428)	4q31		Pakistan		Profound		Riazuddin et al. 2000
DTNB27 (605818)	2q23-q31						Pulleyn et al, 2000
DFNB28	22q13		Palestine	Prelingual	Profound		Walsh et al, 2000
DFNB29 (605608)	21q22	CLDN14	Pakistan		Profound		Wilcox et al, 2001
DFNB30	10p	MYO3A					Karen Avraham, Mary-Claire King, unpublihed Walsh et al., 2002

X-Linked NSHL

The clinical picture for the DFN2 locus (Xq22) is severe to profound hearing impairment which affects all frequencies in males and mild to moderate sensorineural hearing loss or normal hearing in carrier females (Tyson et al. 1996).  For the DFN3 locus [Xq21.1 (POU3F4)], affected males have mixed conductive and sensorineural hearing loss associated with "gushers" at stapes surgery.  Approximately 50% of carrier females have either sensorineural or mixed hearing loss (de Kok et al. 1995).  For the DFN4 locus (Xp21.2), males have congenital hearing loss affecting all frequencies and carrier females have adulthood onset with mild to moderate high frequency hearing impairment (Lalwani et al. 1994).  In kindreds segregating DFN6 (Xp22) affected males have postlingual onset in the 1st decade of life with hearing loss mainly involving the high frequencies. The hearing loss later evolves to severe or profound hearing loss involving all frequencies.  Affected carrier females have a moderate hearing loss that involves the high frequencies, with onset usually in the 4th decade of life. (del Castillo et al.1996).
 

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