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Genetics of the Voice

Robert Thayer Sataloff and Mary J. Hawkshaw

The genetics of voice is a fascinating subject for speculation. Unfortunately, it has been a challenging area of research, and exciting progress has been made only in the last several years. When this chapter was written for the second edition of this book, a computer search of 8 009 307 references in four databases (MEDLINE, Health, AIDS Line, and Cancer Lit) was carried out using the key words: hereditary, genetics, voice, voice disorders, and familial. The computer search produced only 5 references,^1–5 only 3 of which really discussed hereditary voice disorders.^2,3,5

Other conditions discussed in earlier versions of this chapter were identified through the author’s clinical experience, various articles, and a valuable text.⁶ Fortunately, for the fourth edition, review of the content and references contained in numerous medical and speech-language pathology textbooks, reference texts on human genetics, and numerous publications that have appeared during the last 2 decades has shown substantial progress in our mastery of traditional medical genetics of voice disorders. In addition, remarkable achievements have begun in voice-related molecular genetics and genomics.

Normal Voice

Genetic factors do influence vocal quality. This has been recognized anecdotally in families and even nationalities (Italians, Welsh, Russians, and others). If one assumes that function is related to structure, the association of voice quality and genetic factors is intuitively comfortable. It is generally accepted that physical characteristics are genetically determined. If these include the size of the laryngeal cartilages, vocal fold length and structure, size and shape of the supraglottic vocal tract, and phenotypic similarities elsewhere in the vocal mechanism, then one might expect similarities in voice quality. If we postulate additional similarities in brain development, musical perception, and neuromotor control, the notion becomes even more attractive. However, in order to be credible, these issues require further study, and careful separation of genetic factors from environmental influences on development.

Some of the most interesting studies to date have looked at voice function in twins. In general, monozygotic twins have similar voices. Dizygotic twins appear to show the same differences that would be expected among any children of the same age.⁷ Coon and Carey⁸ studied genetic and environmental determinants of musical ability in twins. Because there is more to vocal quality and ability than vocal fold structure alone, such studies are relevant when studying the genetics of voice. Coon and Carey examined monozygotic and dizygotic twins and found evidence of hereditable variation, although environment appeared to be a more important factor than heredity. Kalmus and Fry⁹ studied dysmelodia (inability to sing on tune) and found it to be hereditable as an autosomal dominant trait with imperfect penetrance. They speculated that their findings seemed to indicate the existence of some deep structure of tonality perception, comparable with Chomsky’s deep language structure.

Although Bernstein and Schlaper¹⁰ began looking at the genetic influences on the voice as early as 1922, and Schilling,^11,12 Seeman,¹³ Gedda, Bianchi, and Bianchi-Neroni,¹⁴ and others carried out subsequent work, the complexities of genetic research in humans have left most of the relevant questions unanswered.

Pathological Voice and Syndromes

In addition to the voice quality characteristics that appear to be genetically transmitted in healthy individuals, many pathological conditions are associated with specific genetic voice dysfunctions.¹⁵ For example, raspy voice quality has been recognized in hyalinosis cutis et mucosae,^16–18 Opitz BBB/G compound syndrome,^19–22 pachyonychia congenita syndrome,^23–25 Werner’s syndrome,^26,27 William’s syndrome,^28–31 and other conditions. High-pitched voice occurs in Bloom syndrome,^32–35 chondrodystrophic myotonia,^36–39 deletion (5p) syndrome,⁴⁰ Dubowitz syndrome,^41,42 and Seckel syndrome.⁴³ Low-pitched voice has been observed in cutis laxa syndrome,^44–46 de Lange syndrome,^47–49 deletion (18q) syndrome,^50–53 mucopolysaccharidoses (types I-H, II, III, VI), and Weaver syndrome.^54,55 Other voice abnormalities have been observed in myotonic dystrophy syndrome,^15,56 and in hereditary dystonias that may be associated with spasmodic dysphonia. A dominant form of spinal muscular atrophy associated with distal muscle atrophy, vocal fold paralysis, and sensorineural hearing loss has been reported. Familial vocal fold dysfunction associated with digital anomalies also exists. Verma et al described familial male pseudohermaphroditism with female external genitalia, male habitus, and male voice.² Urbanova reported familial dysphonia,³ and Friol-Vercelletto et al reported familial oculopharyngeal muscular dystrophia with associated abnormal voice.⁵ A variety of other genetic conditions have been associated with voice abnormalities, including Cri du Chat syndrome,^57,58 Plott syndrome,⁵⁹ Ehlers-Danlos syndrome,⁶⁰ Huntington’s chorea,^61,62 von Recklinghausen’s neurofibromatosis⁶³ (hoarseness and dysphagia), Hunter’s and Hurler’s syndromes (hoarseness due to laryngeal deposition of mucopolysaccharide metabolites),⁶⁴ a variety of craniofacial anomalies (Down’s syndrome, Crouzon disease, and others), and various short stature syndromes.⁶⁵ Hence, evidence for the existence of a genetic component to vocal quality is compelling, and fascinating new studies reflect exciting growth in this important field. Richmon et al⁶⁶ reported 2 cases of patients presenting to an otolaryngologic clinic for evaluation of dysphonia. Both patients were found to have tongue hypermobility; both patients were diagnosed subsequently with Ehlers-Danlos syndrome, a group of related hereditary connective tissue diseases.

Spring et al⁶⁷ evaluated 2 families known to have autosomal dominant hereditary sensory neuropathy (HSN-1), a genetically heterogeneous group of disorders associated with chronic cough and gastroesophageal reflux disease (GERD). Many patients with chronic cough develop dysphonia from vocal fold trauma. Thirty-eight individuals provided clinical information and blood for genetic analysis. Linkage to chromosome 3p22-p24 was found in both families. However, there was no linkage to loci for HSN-1 (known). The authors described this family as a novel variant of HSN-1 with distinctive coughs associated with involvement of the upper aerodigestive tract.

Sharma and Franco⁶⁸ reported that several genetic mutations have been identified as associated with different forms of dystonia and may result in spasmodic dysphonia. They pointed out that the pathogenesis of spasmodic dysphonia is not well understood. However, the research of dystonia genetics is ongoing.

Sidtis et al⁶⁹ examined the speech characteristics associated with 3 genotypes of spinocerebellar ataxia (SCA). They obtained voice samples from 26 individuals known to have SCA. The 3 genotypes included were SCA-1, SCA-5, and SCA-6. Speech tasks in­cluded diadochokinesis, word repetition, picture description, and sentence reading. The authors found the SCA-6 genotype to be the most prevalent with articulation being the most impaired. They suggested that voice characteristics might be significant in the differentiation of ataxic subtypes; however, a greater understanding of genetic disorders that affect speech and voice is still needed.

Solot et al⁷⁰ reported that communication disorders are some of the common features of the 22q11.2 microdeletion syndrome. They pointed out that children with the 22q11.2 microdeletion syndrome have multiple medical and developmental issues. The communication disorders include articulation, resonance and voice abnormalities, and language problems. In addition to communication, feeding disorders are often a presenting feature of this syndrome.

Chang and Yung⁷¹ reported a case of a 40-year-old male with hereditary hemorrhagic telangiectasia (HHT) who presented with a 2-year history of hoarseness. They noted that this patient was on anticoagulation therapy. Laryngeal examination revealed vocal fold telangiectasia, vocal fold scar, evidence of previous vocal fold hemorrhage, and dysphonia plica ventricularis. Dysphonia and vocal fold telangiectasia are common in HHT, with this population being at high risk for vocal fold hemorrhage.

In a 2011 report,⁷² Martins et al found evidence of autosomal dominant hereditary transmission of sulcus vocalis. They reported the finding of sulcus vocalis in 4 dysphonic patients from 3 generations of the same family with vertical transmission, affecting both males and females. The authors reported that the findings were consistent with an autosomal dominant inheritance pattern.

Moore et al⁷³ reported that untreated growth hormone deficiency (GHD) is due to genetic GHRH receptor deficiency in adult males, causing high pitch and raspy voice. Their sample size was small (4), and it included untreated adult males. However, they suggested that growth hormones’ effect on vocal fold compliance and size results in a high-pitched voice. Additionally, they pointed out that the time of GHD onset (congenital or acquired) is a determining factor in the voice abnormalities seen.

In 2006, Shriberg et al⁷⁴ reported their evaluation of a mother and daughter known to have 7;13 translocation causing disruption of the transcription gene FOXP2, and both mother and daughter had acquired apraxia of speech and spastic dysarthria, although dysphonia was not a key feature.

Several other studies have reported a correlation between genetic and environment effects on symptoms of dysphonia.^75,76

In 2011, Wilcox et al⁷⁷ described an Australian family with whispering dysphonia that had been assigned the designation of DYT4, a familiar form of dysphonia. They stated that a comprehensive analysis of the causes of the dysphonia was not carried out, nor was the finding of Wilson disease (WND) in 2 siblings in this family explored fully. They obtained DNA samples from 18 family members. Linkage analysis was performed with microsatellite markers, and 6 genes were sequenced: THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND). Results identified 9 living affected members in this family. Neurological evaluation revealed isolated spasmodic dysphonia to severe, generalized dystonia. All loci tested were excluded from genetic analysis. Haplotype analysis of ATP7B (WND) region, revealed 2 parental alleles in 8 siblings of the 2 WND patients (deceased). Two mutated alleles were identified in the WND patients only. The authors identified a missense (c.2297C>G; p.T766R) on these 2 alleles. Five DYT4 family members had neither mutation. The authors concluded that ATP7B did not segregate the dystonia, but suggested 2 separate genetic diseases in this family.

In 2013, Lohmann et al⁷⁸ performed genome-wide linkage analysis in 14 members of the Australian family previously studied in 2011. Findings showed a mutation in TUBB4 (tubulin beta-4; Arg2Gly) caused the DYT4 dysphonia, suggesting that other mutations in TUBB4 might contribute to the development of spasmodic dysphonia, and that abnormal microtubule function has a role in the pathophysiology of dysphonia.

Tanner et al⁷⁹ reported a case of two 79-year-old monozygotic male twins with vocal fold bowing and severe dysphonia. DNA samplings by cheek swabs were obtained, confirming monozygosity for DNA polymorphisms with 10 of 10 concordance for STR DNA markers. Both patients underwent surgical intervention to improve glottic closure, as well as voice therapy. Vocal fold bowing was more pronounced in Twin 1, and Twin 2 obtained greater improvement following treatment. The authors suggested response to voice therapy might have affected outcomes.

An interesting study by Worthey et al⁸⁰ examined the use of whole-exome sequencing (WES) in the assessment of heterogeneous genetic origins in children with childhood apraxia of speech (CAS). Children with CAS, a rare, severe disorder, have deficits of motor speech, cognition, affect, language, and other functions. CAS has been studied widely and found to be a disorder segregating with a mutation in FOXP2

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