Extrarenal features
Twenty-seven genes had no reported extrarenal features in OMIM (11%). These were in the categories for CAKUT (BNC2, DSTYK, MYOCD); Ciliopathies and cystic kidney dieses (DZIP1L, MAPKBP1), Renal proteinuria (ACTN4, APOE, COQ8B, DAAM2, FN1, MAGI2, MYO1E, NPHS1, NUP107, NUP93, PLCE1, PODXL, TBC1D8B, TRPC6) and the Tubulopathies (MAGED2, SLC22A12, SLC2A9).
Most genes affected in genetic kidney disease (221/248, 89%) had several reported extrarenal manifestations (Table 1). Extrarenal involvement was common with all kidney phenotypes, and was found with genes affected in Haematuria (5, 100%), the Ciliopathies and cystic diseases (86, 97%), CAKUT (52, 91%), the Tubulopathies (37, 76%) and Proteinuric kidney diseases (41, 85%).
The median number of extra-renal systems affected was 4 (range 0–10). More extrarenal features were associated with CAKUT (4, 0–10) plus the Ciliopathies and Cystic kidney disease (5, 0–10) than for Haematuria (2, 2–6) plus Proteinuric renal disease (2, 0–6) and the Renal Tubulopathies (3, 0–7).
The number of extrarenal features was greater for CAKUT plus Ciliopathy and Cystic kidney disease genes than for Haematuria, Proteinuric renal disease and the Renal tubulopathy genes for features that were obvious on history or physical examination (p < 0.00001).
Overall, the commonest extrarenal systems affected were Growth and musculoskeletal (164, 66%), Neurological (147, 59%), Ocular (133, 54%), Gastrointestinal and liver (117, 47%) and Head and neck (117, 47%).
CAKUT. The commonest mode of inheritance for the genes affected in CAKUT was monoallelic only (25, 44%) (Table 1). Most affected genes (52, 91%) had extrarenal manifestations. The commonest affected systems were Head and neck (42, 74%), Growth and musculoskeletal (35, 61%), Gastrointestinal and liver (30, 53%), Genitalia (26, 46%), and Cardiac (23, 40%). The commonest manifestations of these systems were microcephaly (15,26%), short stature (10,18%), constipation (7,12%), cryptorchidism (15, 26%), and ventricular septal defect (14, 24%) respectively (Table 2).
Table 2
Commonest features from each disease category
| Commonest Organs or Systems Involved | Commonest Feature from Each System |
CAKUT (n = 57) | Head and Neck (n = 42, 74%) Growth and musculoskeletal (n = 35, 61%) Gastrointestinal (n = 30, 53%) Ocular (n = 28, 49%) Genitalia (n = 26, 46%) Cardiovascular (n = 23, 40%) | Microcephaly (n = 15, 26%) Short stature (n = 10, 18%) Cryptorchidism (n = 15, 26%) Constipation (n = 7, 12%) Ventricular septal defect (n = 14, 24%) |
Ciliopathies and cystic kidney diseases (n = 89) | Neurological (n = 66, 74%) Growth and musculoskeletal (n = 67, 75%) Ocular (n = 64, 72%) Gastrointestinal (n = 51, 57%) Head and neck (n = 46, 52%) | Polydactyly (n = 45, 51%) Molar tooth sign (n = 23, 26%) Inherited retinal degeneration (n = 21, 24%) Low-set ears (n = 18, 20%) |
Haematuria (n = 5) | Ocular (n = 5, 100%) Hearing (n = 4, 80%) | Cataracts (n = 5, 100%) Hearing loss (n = 4, 80%) |
Proteinuric renal disease (n = 49) | Ocular (n = 26, 53%) Neurological (n = 23, 47%) Growth and musculoskeletal (n = 22, 45%) | Seizures (n = 15, 31%) Short stature (n = 9, 18%) Cataracts (n = 7, 14%) |
Tubulopathies (n = 48) | Endocrine (n = 35, 73%) Growth and musculoskeletal (n = 35, 73%) Neurological (n = 26, 54%) | Failure to thrive (n = 17, 35%) Seizures (n = 17, 35%) Metabolic acidosis (n = 17, 35%) |
Renal ciliopathies and Cystic kidney diseases. The commonest mode of inheritance was biallelic only (70,79%). Overall, 86 of the 89 affected genes (97%) had extrarenal manifestations. The commonest affected systems were Growth and musculoskeletal (68, 76%), Neurological (67, 75%), Ocular (66, 74%), Gastrointestinal and liver (53, 60%) and Head and neck (47, 53%) (Table 1). The commonest manifestations of these systems were polydactyly (45, 51%), the molar tooth sign (23, 26%), inherited retinal degeneration (21, 24%), hepatic fibrosis and low-set ears (18, 20%) respectively (Table 2).
Haematuria. The modes of inheritance were monoallelic only (in 2), monoallelic and biallelic (in 2) and X-linked (in one). All five genes in the Haematuria panel had extrarenal manifestations. The commonest affected systems were ocular (5/5, 100%), and hearing (4/5, 80%) (Table 1). The commonest manifestations of these systems were cataracts (5, 100%) and hearing loss (4, 80%) respectively (Table 2).
Proteinuric kidney disease. The commonest mode of inheritance was biallelic only (31, 63%). Overall, 37 of the 50 genes studied (76%) had extrarenal manifestations (Table 1). The commonest affected extrarenal systems were Ocular (26, 53%), Neurological (26, 53%), and Growth and musculoskeletal (25, 51%). The commonest manifestations of these systems were cataracts (5, 100%), seizures (15, 31%), and short stature (9, 18%) respectively (Table 2).
Tubulopathies. The commonest mode of inheritance was biallelic only (24, 50%). Forty-one of the 48 genes (85%) had extrarenal manifestations (Table 1). The commonest affected extrarenal systems were Growth and musculoskeletal (35, 73%) and Neurological (26, 54%). The commonest manifestations of these systems were failure to thrive (17, 35%), and seizures (17, 35%). Endocrine effects were also common (36, 75%) including metabolic acidosis (17, 35%) (Table 2).
Affected systems
Growth and musculoskeletal. Clinical features varied from short stature and failure to thrive to skeletal abnormalities such as polydactyly. Overall the commonest abnormalities were polydactyly and short stature. Polydactyly was associated most often with the genes affected in the Ciliopathies and cystic diseases (45, 51%). Short stature was associated most often with CAKUT (10, 18%) and Renal proteinuria (9, 16%)(Table 2).
Neurological. The commonest neurological abnormalities were intellectual disability or delay, and seizures. Intellectual disability or delay was associated with 61 genes (25%) overall, but was not more frequent with any phenotype. Seizures were associated with the Tubulopathies (17, 35%) and Renal proteinuria (15, 31%).
Head and neck. The commonest Head and neck abnormalities were low-set ears (36, 15%) and microcephaly (35, 14%). Low-set ears were most common in the Ciliopathies and cystic kidney diseases (18, 20%). Microcephaly was mainly found associated with CAKUT (20, 35%).
Ocular. The commonest Ocular abnormalities were hypertelorism (28, 11%) and nystagmus (24, 10%), but these were not found more often with any disease phenotype. Inherited retinal degeneration was common in the Ciliopathies and cystic kidney diseases (21, 24%). Cataracts were found with all disease types and associated with all five haematuria genes.
Gastrointestinal and liver. The commonest Gastrointestinal abnormalities were feeding difficulties (21, 8%), hepatomegaly (17, 7%), and hepatic fibrosis (17, 7%). Hepatic pathology predominated in the genes affected in the Ciliopathies and cystic kidney diseases with hepatic fibrosis (14, 16%) and hepatomegaly (11, 12%).
Genitalia. Genital abnormalities were commonest in the CAKUT and Ciliopathies and Cystic kidney disease panels. The commonest genital abnormality were cryptorchidism (15, 26%) in CAKUT.