Genetic heterogeneity of congenital hearing impairment in Algerians from the Ghardaïa province.

BACKGROUND: Consanguinity rate is high in Algeria, and the population is thus at high risk for genetic diseases transmitted on an autosomal recessive mode. Inherited congenital hearing impairment (HI) is a highly heterogeneous disorder, which affects approximately 1 in 800 Algerian newborns. Several hundreds of genes responsible for deafness have been reported among which more than one hundred are responsible for isolated deafness, of which 19 have already been reported to be involved in the Algerian population. This study focuses on patients from the Ghardaïa province, an ethnically and geographically isolated region of Southern Algeria that has the highest consanguinity rate in the country (56%). METHODS: Eleven families, with at least two related members experiencing moderate to profound congenital HI, were recruited and screened for mutations in known HI genes. RESULTS: A preliminary screening for common mutations in GJB2 and GJB6 identified the prevalent GJB2:c.35delG mutation in four families. Targeted exome sequencing further identified the causal mutations in the remaining seven families: CIB2:c.97C > T; p.(Arg33*), MYO7A:c.470+1G > A; p.(?), and SLC26A4:c.410C > T; p.(Ser137Leu) biallelic mutations in two families each, and a TECTA:c.2743 A > G; p.(Ile915Val) monoallelic mutation in the only family with autosomal dominant transmission of the HI. Of note, the missense mutations of SLC26A4 and TECTA had not been previously reported. CONCLUSION: These results further substantiate the genetic heterogeneity of HI, even in reportedly isolated populations. However, several families may harbor the same mutations as a result of a long history of marriages between relatives. This study has important implications for the HI molecular diagnosis strategy, and to develop genetic counseling for families originating from the Ghardaïa province of Algeria.

Heterogeneity of lung disease associated with NK2 homeobox 1 mutations.

We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.