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Table 2 Clinical data and sequencing results of consanguineous and non-consanguineous patients with MKS and MKS-like phenotypes

From: Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies

Sample Mutation Phenotype
Id Ethnicity Gene Allele 1 Allele 2 OE PK PD DPM CLP DWM Other
Consanguineous
102 + 103 + 244 + 270 Pakistani MKS1 c. 1448_1451dupCAGG MKS1 c. 1448_1451dupCAGG + + +   +   Short neck, low set ears, bilateral talipes, syndactyly, micropenis, situs inversus, congenital heart defect inc. dextrocardia, short femurs and short spindle-shaped tibiae, deformed tongue
264 Jordanian MKS1 c. 1408-35_1408-6del30N c.1408-35_1408-6del30N        diagnosed with MKS
42 + 43 Pakistani TMEM138 c. A287G p.H96R c. A287G p.H96R + +   +    
29A + 33A Pakistani/Mirpuri TMEM67 c. 1575 + 1 G > A c. 1575 + 1 G > A + + + +    
70 Pakistani/Mirpuri TMEM67 c. 1575 + 1 G > A c. 1575 + 1 G > A   +     +  
76 Pakistani/Mirpuri TMEM67 c. 1575 + 1 G > A c. 1575 + 1 G > A + +      
77117 Pakistani TMEM67 c. 1575 + 1 G > A c. 1575 + 1 G > A        diagnosed with MKS
51 Pakistani/Mirpuri TMEM67 c. 870-2A > G c. 870-2A > G +       
73 Pakistani/Mirpuri TMEM67 c. 870-2A > G c. 870-2A > G + +   +    
319 British TMEM67 c. 1392 C > T p.R441C c. 1392 C > T p.R441C   +   +    some dialation of pancreatic ducts, hydrocephalus, posterior fossa cyst
347 Pakistani TMEM67 c. 1392 C > T p.R441C c. 1392 C > T p.R441C        diagnosed with MKS
67FB Pakistani TMEM67 c. 647delA, p.E216fsX221 c. 647delA, p.E216fsX221 + +   + +   
P95 Pakistani TMEM67 c. 1127A > C p.Q376P c. 1127A > C p.Q376P + +   +    
125 Omani TMEM67 c. 383_384delAC p.H128fsX140 c. 383_384delAC p.H128fsX140 + + +    +  
170 Turkish TMEM67 c. 1674 + 1 G > AN c. 1674 + 1 G > AN        diagnosed with MKS
205 Chinese TMEM67 c. 1615 C > T p.R549CN c. 1615 C > T p.R549CN   +   +    hypoplastic cerebellum, small fourth ventricle with large cisterna magna, small defect in superior aspect of occipital bone
C28 Pakistani TMEM67 c. 274 G > A p.G92RN c. 274 G > A p.G92RN        MTS, coloboma, mental retardation
39 Pakistani/Mirpuri CEP290 c. 1429 C > T p.R477XN c. 1429 C > T p.R477XN   +   +    
292 Pakistani CEP290 c. 954delT p.S318fs16XN c. 954delT p.S318fs16XN +       
333 Pakistani CEP290 c. 5744insT p.G1915FfsX1N c. 5744insT p.G1915FfsX1N +       
207 Pakistani RPGRIP1L c. 1945 C > T p.R649XN c. 1945 C > T p.R649XN + + +     small cerebellum
336 Pakistani RPGRIP1L c. 1945 C > T p.R649XN c. 1945 C > T p.R649XN        diagnosed with MKS
158 Pakistani CC2D2A c. 3540delA p.R1180SfsX6N c. 3540delA p.R1180SfsX6N + + + + +   low set ears, pulmonary hypoplasia, intestinal malrotation, markedly enlarged pancreas- irregular ducts on histology, brain shows dilated fourth ventricle with small cerebellum, poorly developed pyramidal tracts and some possible dysplasia in the basal ganglia
180 Pakistani CC2D2A c. 3540delA p.R1180SfsX6N c. 3540delA p.R1180SfsX6N + + +    +  
261 Jordanian TMEM237 c. 1066_1067dupC p.Q356PfsX23 c. 1066_1067dupC p.Q356PfsX23        meningomyelocele, developmental delay, cortical visual impairment
178 Pakistani/Mirpuri TMEM67 c. 1615 C > T p.R549CN not detected        diagnosed with MKS
16 + 17 Pakistani CC2D2A c. 685_687delGAA het p.E229del not detected   +   +    
66 F1 + 66 F2 Pakistani CC2D2A c. 685_687delGAA het p.E229del not detected + + + +    absent uterus, micrognathia, bilateral talipes, low set ears, wide spread eyes
Non-Consanguineous
106 British MKS1 c. 1408-35_1408-7del29 c. 1408-35_1408-7del29 + + + +    
77172 Finnish MKS1 c. 1408-35_1408-7del29 c. 811delC p.H271fsX29N        diagnosed with MKS
74699 British MKS1 c. 1408-35_1408-7del29 c. 1408-35_1408-7del29        diagnosed with MKS
162 + 163 British TMEM216 c. 253 C > T p.R85X c. 253 C > T p.R85X + + + + +   facial dysmorphism, postural deformities of limbs, small perimembranous ventricular septal defect, intestinal malrotation
176 + 177 British TMEM67 c. 1426 C > T p.P476S†† c. 2440–3 C > A + + + +    flexion deformity of elbows and wrists, low set ears
186 British TMEM67 c. 755 T > C p.M252T c. 653 G > T p.R208X††† + +      
302 British TMEM67 c.755 T > C p.M252T c.651 + 5 G > A p.V217VfsN   +   +   + agenesis of corpus callosum
83527 Norwegian-Indian TMEM67 c. 755 T > C p.M252T c. 2882 C > A p.S961YN + +   +    
74406a + b   TMEM67 c. 1351 C > T p.R451X c. 2108 T > A p.V673A   +   +    mental retardation, retinal coloboma
210 + 239 Dutch CEP290 c. 679_680delGA p.E227SfsX2 c. 1984 C > T p.Q662X   +   +   + abnormal cerebellum, wide nasal bridge, extended abdomen, thoracic and abdominal situs inversus, intestinal rotation, small bladder, uterus duplex
153 + 154 French CEP290 a c. 2251 C > T p.R751X c. 4864insTdelCG p.R1622FfsX9N   +      
166 British RPGRIP1L c. 1829A > C p.H610P c. 721_724delAATG p.N241fsX25 + + +    +  
128 British CC2D2A c. 3544 T > C p.W1182R c. 3774_3774insT p.E1259fsX1        diagnosed with MKS
36 + 36A Pakistani/Gujarati RPGRIP1L c. 466 C > T p.R156C*N not detected + +      
111 + 112 Portuguese CEP290 c. 1451delA p.K484fsX8 not detected + + +     
202 British CC2D2A c. 685_687delGAA p.E229del** not detected + +      craniofacial abnormalities related to oligohydramnios, bone-cartilage junctions showed disarray
  1. CLP, cleft lip/palate; DPM, ductal plate malformation; DWM, Dandy-Walker malformation; OE, occipital encephalocele; PD, polydactyly; PK, polycystic kidneys; * in cis with c. 3790 G > A het p.D1264N, ** in cis with c. 3893 T > A p.V1298D; p.R85X allele was present in 2/10,266 European/African/American controls in the Exome Variant Server (EVS) database, †† p.P476S allele present in 6/7,012 European/American controls (EVS), ††† p.R208X allele present in 8/7,012 European/American controls (EVS). The remaining changes are excluded in about 10,000 European/African/American controls (EVS). N indicates a novel mutation that has not previously been reported. a indicates that affected siblings 153 + 154 are compound heterozygotes for CEP290 mutations, but both also carry a third heterozygous putative pathogenic mutation in TMEM216 c. 188 T > G p.L63R.