Alternative titles; symbols
ORPHA: 494444; DO: 0110541;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q31.3 | Deafness, autosomal dominant 1, with or without thrombocytopenia | 124900 | Autosomal dominant | 3 | DIAPH1 | 602121 |
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-1 with or without thrombocytopenia (DFNA1) is caused by heterozygous mutation in the DIAPH1 gene (602121) on chromosome 5q31.
DFNA1 is an autosomal dominant form of progressive hearing loss with onset in the first decade. Some patients have mild thrombocytopenia and enlarged platelets, although most of these individuals do not have significant bleeding tendencies (summary by Neuhaus et al., 2017).
Konigsmark et al. (1971) studied 3 families with low frequency hearing loss in an autosomal dominant pedigree pattern.
In a large Costa Rican family, Leon et al. (1981) described many cases of low frequency autosomal dominant deafness which differed from that previously reported in its earlier onset (first decade) and its progression to more profound deafness. Although the audiometric results indicated an apical initiation of the pathology, as might result from endolymphatic hydrops, presumably produced by alterations in the stria vascularis or from labyrinthine otosclerosis, no bone histology was available to identify the precise structures affected. In later studies, Leon et al. (1992) indicated that the deafness was primary (i.e., nonsyndromal) and postlingual (with onset at about age 10 years, after language and speaking were learned). By age 30, intelligence, fertility, and life expectancy were normal. The family traced its ancestry to an affected founder by the name of Monge, who was born in Costa Rica in 1754.
Low frequency hearing loss is said to occur in several sensorineural hearing disorders such as Meniere disease, myxedema, and inner ear malformations, and in conductive hearing disorders resulting from either fixation or partial disruption of the ossicular chain (Parving, 1984).
Deafness with Thrombocytopenia
Stritt et al. (2016) reported 2 unrelated families in which a total of 8 patients had early-onset high frequency sensorineural hearing loss associated with macrothrombocytopenia. Sensorineural hearing loss was detected either at birth or in the first decade of life, but progressed rapidly to a severe defect requiring bilateral hearing aids in all patients. Only 2 patients, both females, had bleeding symptoms, including menorrhagia and postpartum bleeding; the other patients did not have excessive bleeding. Platelets from 3 patients showed normal aggregation and granule secretion. Electron microscopy showed that the enlarged platelets were typically round and contained some abnormal vacuoles, membrane complexes, and abnormally distributed alpha-granules. Six patients had asymptomatic mild neutropenia, and 4 had iron deficiency anemia that corrected with dietary iron supplementation. The 2 index patients were ascertained from a cohort of 702 index cases with bleeding or platelet disorders of unknown genetic basis who underwent high-throughput sequencing.
Neuhaus et al. (2017) reported 7 patients from 2 unrelated families with DFNA1 associated with thrombocytopenia. The patients developed progressive and severe sensorineural hearing loss in the first decade of life. Advanced studies were consistent with cochlear hearing loss, which affected mid and high frequencies. All patients had thrombocytopenia, sometimes with enlarged platelets, but this was an incidental finding and none had clinical symptoms of thrombocytopenia.
Ganaha et al. (2017) reported a Japanese family in which 8 members over 4 generations had symmetric sensorineural hearing loss. The hearing loss was initially mild, affecting only high frequencies, but progressed to severe to profound hearing loss affecting all frequencies. No vestibular symptoms were reported by the patients. Blood studies were performed on 7 patients, 6 of whom were found to have macrothrombocytopenia without a bleeding tendency. Macrothrombocytopenia appeared to be progressive.
The transmission pattern of DFNA1 with or without thrombocytopenia in the families reported by Leon et al. (1992) and Stritt et al. (2016) was consistent with autosomal dominant inheritance.
Nurden et al. (2018) reported management of thrombocytopenia in a patient with DFNA1 with thrombocytopenia in the setting of 2 laparoscopic surgeries to treat infertility, surgical management of an ectopic pregnancy, pregnancy, and peripartum. The patient had a history of hearing deficiency since childhood, asymptomatic and mild neutropenia, and thrombocytopenia with increased platelet volume. To manage bleeding risk, tranexamic acid was given 3 hours before and 3 hours after each laparoscopic surgery (peritubal adhesion screening and neosalpingostomy) and then 3 times daily for the next 2 days. No bleeding was observed. After unilateral salpingectomy for an ectopic pregnancy, the same treatment protocol was used and prevented bleeding. The patient became pregnant a year later, and platelets, which were monitored throughout pregnancy, were at their lowest level between 16 and 26 weeks' gestation. She successfully received an epidural for anesthesia, and had a vaginal delivery without excessive peripartum blood loss. Platelet count was performed on the cord blood as a screen for thrombocytopenia in the newborn and was normal.
Leon et al. (1992) mapped the locus for deafness in the Costa Rican family described by Leon et al. (1981) to chromosome 5q31, between markers IL9 (146931) at 5q31-q32 and GRL (138040) at 5q31. The maximum lod score with IL9 was 13.55 at theta = 0.06. They indicated that the IL9 and GRL genes are separated by about 7 cM.
The form of autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive hearing loss in the large Costa Rican kindred studied by Leon et al. (1981, 1992) was designated DFNA1. Lynch et al. (1997) mapped the DFNA1 gene in this kindred to a region of 1 cM on 5q31 by linkage analysis and constructed a complete 800-kb bacterial artificial chromosome (BAC) contig of the linked region. They compared the sequences of these BACs with known genes and expressed sequence tags (ESTs) from all available databases. A previously unidentified human gene homologous to the Drosophila gene 'diaphanous' and a mouse gene was revealed by the genomic sequence of 3 BACs. The human diaphanous gene (602121) was screened for mutations in members of the Costa Rican M family by means of SSCP analysis. Sequencing of variant bands revealed a guanine-to-thymine substitution in the splice donor of the penultimate exon of DFNA1 in affected members of the M kindred (602121.0001). The base substitution disrupted the canonical splice donor sequence AAGgtaagt and resulted in insertion of 4 nucleotides in the transcript, a frameshift, and loss of the C-terminal 32 amino acids of the protein. All 78 affected members of the M kindred were heterozygous for the mutation. The site was wildtype in 330 control individuals with normal hearing (660 chromosomes) of the following ancestries: 12 Costa Ricans unrelated to the M family, 94 Latin Americans from other countries, 32 Spanish, 154 Europeans (other than Spanish) and North Americans of European ancestry, and 38 African Americans. By RT-PCR of cochlear RNA using PCR primers that amplify the region of the gene that harbored the mutation in family M, Lynch et al. (1997) confirmed expression of human diaphanous in the cochlea. The authors speculated that the biologic role of this human diaphanous homolog in hearing is likely to be the regulation of actin polymerization in hair cells of the inner ear.
In 8 affected individuals from 2 unrelated families with DFNA1 with thrombocytopenia, Stritt et al. (2016) identified a heterozygous truncating mutation in the DIAPH1 gene (R1213X; 602121.0005). The mutation, which was found by high-throughput sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Megakaryocytes derived from 1 of the patients showed defective maturation and defective proplatelet formation compared to controls. Mutant platelets also showed an altered cytoskeleton with disorganized microtubules, aberrant organization of F-actin, increased microtubule content, and increased microtubule stability. Stritt et al. (2016) hypothesized that the R1213X mutation results in constitutive activation of DIAPH1 with cytoskeletal defects causing reduced proplatelet formation.
In affected members of 2 unrelated families with DFNA1 with thrombocytopenia, Neuhaus et al. (2017) identified heterozygous truncating mutations in exon 27 of the DIAPH1 gene, R1213X and a 2-bp deletion (602121.0006). The mutation in the first family was found by next-generation sequencing and confirmed by Sanger sequencing; the mutation in the second family was found by targeted Sanger sequencing of the DIAPH1 gene. Functional studies of the variants were not performed, but Neuhaus et al. (2017) hypothesized that since exon 27 is the penultimate exon, the mutant transcript likely escapes nonsense-mediated mRNA decay, resulting in the production of a truncated protein with a gain-of-function effect. Neuhaus et al. (2017) also found expression of the DIAPH1 gene in mouse cochlea, spiral ganglion neurons, and the cochlear nerve.
In affected members of a Japanese family segregating autosomal dominant deafness and thrombocytopenia, Ganaha et al. (2017) identified heterozygosity for the R1213X mutation in the DIAPH1 gene. The mutation, which was identified by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
Parving (1984) suggested that Konigsmark syndrome is a sensorineural disorder 'transmitted by a dominant gene with complete penetrance.' In another group of patients, dominant inheritance with incomplete penetrance was considered likely and the type of deafness--sensorineural or conductive--could not be determined. Parving (1984) suggested that these patients have a mixed form 'caused by an early arrest in the embryological development of both the ossicles and the cochlea.' Of 6 patients of the latter type, a 'carrier state' was found in the mother of 3, and in 3 others the father and a brother were affected.
Ganaha, A., Kaname, T., Shinjou, A., Chinen, Y., Yanagi, K., Higa, T., Kondu, S., Suzuki, M. Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease. Am. J. Med. Genet. 173A: 2826-2830, 2017. [PubMed: 28815995] [Full Text: https://doi.org/10.1002/ajmg.a.38411]
Konigsmark, B. W., Mengel, M. C., Berlin, C. I. Dominant low-frequency hearing loss: report of three families. Laryngoscope 81: 759-771, 1971. [PubMed: 5157378] [Full Text: https://doi.org/10.1288/00005537-197105000-00017]
Leon, P. E., Bonilla, J. A., Sanchez, J. R., Vanegas, R., Villalobos, M., Torres, L., Leon, F., Howell, A. L., Rodriguez, J. A. Low frequency hereditary deafness in man with childhood onset. Am. J. Hum. Genet. 33: 209-214, 1981. [PubMed: 7211837]
Leon, P. E., Raventos, H., Lynch, E., Morrow, J., King, M.-C. The gene for an inherited form of deafness maps to chromosome 5q31. Proc. Nat. Acad. Sci. 89: 5181-5184, 1992. [PubMed: 1350680] [Full Text: https://doi.org/10.1073/pnas.89.11.5181]
Lynch, E. D., Lee, M. K., Morrow, J. E., Welcsh, P. L., Leon, P. E., King, M.-C. Nonsyndromic deafness DFNA1 associated with mutation of the human homolog of the Drosophila gene diaphanous. Science 278: 1315-1318, 1997. [PubMed: 9360932]
Neuhaus, C., Lang-Roth, R., Zimmermann, U., Heller, R., Eisenberger, T., Weikert, M., Markus, S., Knipper, M., Bolz, H. J. Extension of the clinical and molecular phenotype of DIAPH1-associated autosomal dominant hearing loss (DFNA1). Clin. Genet. 91: 892-901, 2017. [PubMed: 27808407] [Full Text: https://doi.org/10.1111/cge.12915]
Nurden, P., Nurden, A., Favier, R., Gleyze, M. Management of pregnancy for a patient with the new syndromic macrothrombocytopenia, DIAPH1-related disease. Platelets 29: 737-738, 2018. [PubMed: 29985732] [Full Text: https://doi.org/10.1080/09537104.2018.1492710]
Parving, A. Inherited low-frequency hearing loss: a new mixed conductive/sensorineural entity? Scand. Audiol. 13: 47-56, 1984. [PubMed: 6719015] [Full Text: https://doi.org/10.3109/01050398409076257]
Stritt, S., Nurden, P., Turro, E., Greene, D., Jansen, S. B., Westbury, S. K., Petersen, R., Astle, W. J., Marlin, S., Bariana, T. K., Kostadima, M., Lentaigne, C. A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood 127: 2903-2914, 2016. [PubMed: 26912466] [Full Text: https://doi.org/10.1182/blood-2015-10-675629]
Willems, P. J. Genetic causes of hearing loss. New Eng. J. Med. 342: 1101-1109, 2000. [PubMed: 10760311] [Full Text: https://doi.org/10.1056/NEJM200004133421506]