Table 3.
Patients with double/triple heterozygous or homozygous variants. Predictions of pathogenicity of the variants are in Table 2. Heterozygous variants in these patients are not shown. XLR, X-linked recessive; Homo, homozygous. Novel variants are bolded. § This intronic change generates a cryptic donor splice site, which inserts an intronic sequence between exons 9 and 108. The term ‘triple heterozygous’ signifies the presence of three variants in the same gene, as in Patients 13 and 14. As phasing was done, it is unclear on which allele the triple heterozygous variants resided, as pathogenic compound heterozygous variants could result in autosomal recessive disease.
| Patient | First | Second | Third | Clinical Assessment |
|---|---|---|---|---|
| 1 Homo |
C1orf127:c.337C>T (p.Arg113Ter) | C1orf127:c.337C>T (p.Arg113Ter) | - | Heterotaxy, asplenia, midline liver, pulmonary stenosis, interrupted inferior vena cava, bilateral superior vena cava, and right aortic arch. |
| 2 Homo |
C1orf127:c.337C> (p.Arg113Ter) | C1orf127:c.337C> (p.Arg113Ter) | - | Dextrocardia, pulmonary stenosis, respiratory infections. Parents are heterozygous for EP400 and asymptomatic. Family members with congenital heart anomalies. |
|
EP400:c.323C>T (p.Ala108Val) rs762116055-Likely benign |
EP400:c.323C>T (p.Ala108Val) rs762116055 - Likely benign |
- | ||
| 3 | CCDC39:c.1073C>T (p.Thr358Ile) | CCDC39:c.1076A>C (p.Lys359Thr) | - | Prematurity (32 weeks’ gestation) with persistent atelectasis. Parental studies revealed the variants are in cis phase. |
| 4 Homo |
CCDC39:c.1167+1261A>G | CCDC39:c.1167+1261A>G | - | Two cousins with homozygosity and diagnostic features of PCD. § |
| 5 | CCDC39:c.1363-3delC | CCDC39:c.1781C>T (p.Thr594Ile) | - | Clinical features of PCD. § |
| 6 | CCDC40:c.1445G>A (p.Cys482Tyr) | CCDC40:c.257A>G (p.Tyr86Cys) | - | Heterotaxy syndrome (isomerism). |
| 7 | CCDC40:c.850G>C (p.Asp284His) | CCDC40:c.697G>A (p.Asp233Asn) | - | Recurrent sinusitis. |
| 8 Homo |
CCDC40:c.62G>T (p.Gly21Val) | CCDC40:c.62G>T (p.Gly21Val) | - | Two siblings with sinopulmonary infections (including chronic otorrhea) from early infancy with ultrastructural defects in the cilia (significant microtubular disorganizations, including distorted dynein arms and absent inner dynein arms). |
| 9 Homo |
CEP104:c.2092G>A (p.Glu698Lys) | CEP104:c.2092G>A (p.Glu698Lys) | - | Joubert syndrome 25 (MIM#616781). Parents are asymptomatic carriers. |
| 10 Homo |
DNAH5:c.4807C>A (p.Pro1603Tyr) | DNAH5:c.4807C>A (p.Pro1603Tyr) | - | Two sisters with bronchiectasis and chronic sinusitis. Parents are heterozygous and asymptomatic. Mother had recurrent abortions and an ectopic pregnancy. |
| 11 Homo |
DNAH5:c.5503C>T (p.Gln1835Ter) | DNAH5:c.5503C>T (p.Gln1835Ter) | - | Two sisters with chronic respiratory infections and ultrastructural defects in the cilia (significant microtubular disorganizations, including distorted outer dynein arms). |
| 12 | DNAH8:c.3289A>G (p.Ile1097Val) | DNAH8:c.5789G>A (p.Arg1930His) | - | Clinical features of PCD. |
| 13 | DNAH11:c.2570G>A (p.Arg857Gln) | DNAH11:c.9305G>A (p.Gly3102Asp) | DNAH11:c.13010G>A (p.Ser4337Asn) | Recurrent respiratory infections from childhood and non-motile sperms. Since parents were not tested, phasing of variants could not be performed. |
| 14 | DNAH11:c.13120G>A (p.Val4374Met) | DNAH11:c.4945-12T>C | DNAH11:c.5132A>G (p.Gln1711Arg) | Chronic sinusitis. Since parents were not tested, phasing of variants could not be performed. |
| 15 | DNAH11:c.8230C>T (p.Arg2744Cys) | DNAH11:c.11839+1G>A | - | Situs inversus totalis with dextrocardia. |
| 16 | DRC1:c.1090G>A (p.Glu364Lys) | DRC1:c.2081G>C (p.Arg694Thr) | - | Clinical features of PCD. Parents are first cousins. The mother also has clinical features of PCD with the same two variants. The father is not tested. |
| 17 | HYDIN:c.1003G>T (p.Val335Leu) | HYDIN:c.9638C>G (p.Pro3213Arg) | - | Clinical features of PCD. |
| 18 | HYDIN:c.1003G>T (p.Val335Leu) | HYDIN:c.9638C>G (p.Pro3213Arg) | - | Prematurity (33 weeks’ gestation) with clinical features of PCD. |
| DNAAF3:c.1053+5G>C | DNAAF3:c.1116+5G>C | - |