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Our report clarifies the role of ATP6V1B2 in patients with deafness and onycho‐osteodystrophy and confirms that a recurring ATP6V1B2 c.1516C>T [p.(Arg506*)], variant causes dominant deafness–onychodystrophy (DDOD) syndrome.
Dominant deafness–onychodystrophy (DDOD; MIM 124480), deafness–onychodystrophy–osteodystrophy–mental retardation–seizures (DOORS; MIM 220500), and Zimmermann–Laband (ZL; MIM 135500) syndromes are characterized by the association of sensorineural deafness and onychodystrophy. DDOD and ZL are autosomal dominant conditions, and DOORS is autosomal recessive. Patients with DDOD syndrome have normal development and cognitive functions 1, 2, 3, while those with DOORS and ZL syndromes, intellectual disabilities and seizures have been reported 4, 5. Additional findings in ZL syndrome include gingival enlargement, hypertrichosis, joint hyperextensibility, and hepatosplenomegaly. Pathogenic variants in TBC1D24 (MIM 613577) 4 and KCNH1 (MIM 603305) 5 cause DOORS and ZL syndromes, respectively. A pathogenic c.1516C>T [p.(Arg506*)] variant in ATP6V1B2 has recently been reported to cause DDOD syndrome in three simplex cases 6. In a subsequent report, however, another ATP6V1B2 variant c.1454G>C [p.(Arg485Pro)] was reported to cause ZL syndrome in two simplex cases 5. It remains unknown whether reported patients with DDOD syndrome and an ATP6V1B2 variant had additional findings of ZL syndrome because those details were not available in the original report 6. Here, we describe our clinical and molecular studies in the diagnosis of a simplex patient with deafness–onychodystrophy.
The proband is the second child of nonconsanguineous healthy Guatemalan parents. Two sisters are healthy (Fig. (Fig.1).1). He was born via normal spontaneous vaginal delivery at term following an uneventful pregnancy. Birth weight was 3060 g. Initial examination revealed bilateral digital anomalies in hands and feet. Audiological examination by auditory brainstem responses (ABR) at 1 year of age indicated profound bilateral sensorineural hearing impairment. At the age 12 years, his height, weight, and head circumference measure 146 cm (25–50 percentile), 48 kg (75–90 percentile), and 56 cm (90 percentile), respectively. He has a high forehead with dolichocephaly, bilateral triphalangeal thumbs without nails, hypoplastic fingernails from second to fifth fingers, flat feet with absent toenails (Fig. (Fig.1).1). He does not have gingival hyperplasia, hypertrichosis, organomegaly, or joint hyperextensibility. Neurological examination followed by EEG, brain CT scan, and MRI did not show abnormalities. He does not communicate orally, but a rudimentary sign language was present. Bilateral sensorineural severe‐profound hearing loss was documented (Fig. (Fig.2).2). Family history was negative for deafness, nail dysplasia, and intellectual disabilities.
This study was approved by the University of Miami Institutional Review Board (USA) and Guatemala National Health Ethics Committee. After written informed consents were collected, DNA was extracted from peripheral blood samples by standard procedures. Whole‐exome sequencing in the proband was performed as previously reported 7.
Whole exome sequencing (WES) was performed only in the proband 7. Targeted exonic regions were covered 100%, 96%, and 88% in read depth of 1X, 5X, and 10X, respectively. In total, 82,594,033 number of reads, 92,131 base substitutions (synonymous, nonsynonymous, intronic), and 8277 insertions/deletions were detected. Variants were filtered as previously published 7 in all modes of inheritance patterns, followed by filtering for Mendelian genes previously reported in OMIM Morbid.
The proband was found to be heterozygous for c.1516C>T [p.(Arg506*)] in ATP6V1B2 (NM_001693.3). Sanger sequencing confirmed the variant only in the proband and excluded the variant in parents and sisters (Fig. (Fig.2).2). We did not test the parental identities with additional markers.
Deafness and onychodystrophy, although major diagnostic findings, fail to guide specific clinical diagnosis. Seizures and intellectual disabilities are used to differentiate DOORS from DDOD 1, 4, 6, 8. Neurological and behavioral problems are common in children with severe‐profound hearing loss. For instance in our patient, severe‐profound prelingual sensorineural hearing loss and a long period of auditory deprivation without specific education led to a phenotype with limited social interactions. Time of deprivation, and nutritional and socioeconomic status have been associated with developmental delay and cognitive problems in deaf individuals 9, 10. While ZL syndrome has additional features such as gingival enlargement and hypertrichosis, differential diagnosis is not always straightforward.
Interestingly, pathogenic variants in ATP6V1B2 have been reported to cause both DDOD and ZL syndromes 5, 6. Table 1 summarizes phenotypic findings in ATP6V1B2‐related disorders. It should be noted that the information about differentiating clinical features between DDOD and ZL syndromes was missing in the report associating an ATP6V1B2 variant with DDOD syndrome 5 (Table 1). In our patient, the p.(Arg506*) variant does not cause gingival hyperplasia, hypertrichosis, or organomegaly and is associated with DDOD syndrome. Individuals with the p.(Arg485Pro) variant on the other hand were reported to develop these additional findings and are diagnosed with ZL syndrome.
The authors declare no conflict of interests.
All authors contributed extensively to the work presented in this study. IM, CC, GB, and MT: performed clinical examination, interpreted the data, and wrote the manuscript. MH, NM, JF, and FBC: draw blood samples, obtained DNA, and conducted genetic studies.
Support for this research was provided by INVEGEM, The Rozas‐Botran Foundation from Guatemala, and supported by National Institute of Health grants R01DC009645 and R01DC012836 to MT.