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

Szymanska, Katarzyna; Berry, Ian; Logan, Clare V; Cousins, Simon RR; Lindsay, Helen; Jafri, Hussain; Raashid, Yasmin; Malik-Sharif, Saghira; Castle, Bruce; Ahmed, Mushtag; Bennett, Chris; Carlton, Ruth; Johnson, Colin A

doi:10.1186/2046-2530-1-18

Cilia

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_1408-6del30^N	c.1408-35_1408-6del30^N							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 > A^N	c. 1674 + 1 G > A^N							diagnosed with MKS
205	Chinese	TMEM67	c. 1615 C > T p.R549C^N	c. 1615 C > T p.R549C^N		+		+			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.G92R^N	c. 274 G > A p.G92R^N							MTS, coloboma, mental retardation
39	Pakistani/Mirpuri	CEP290	c. 1429 C > T p.R477X^N	c. 1429 C > T p.R477X^N		+		+
292	Pakistani	CEP290	c. 954delT p.S318fs16X^N	c. 954delT p.S318fs16XN	+
333	Pakistani	CEP290	c. 5744insT p.G1915FfsX1^N	c. 5744insT p.G1915FfsX1^N	+
207	Pakistani	RPGRIP1L	c. 1945 C > T p.R649X^N	c. 1945 C > T p.R649X^N	+	+	+				small cerebellum
336	Pakistani	RPGRIP1L	c. 1945 C > T p.R649X^N	c. 1945 C > T p.R649X^N							diagnosed with MKS
158	Pakistani	CC2D2A	c. 3540delA p.R1180SfsX6^N	c. 3540delA p.R1180SfsX6^N	+	+	+	+	+		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.R1180SfsX6^N	c. 3540delA p.R1180SfsX6^N	+	+	+			+
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.R549C^N	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.H271fsX29^N							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.V217Vfs^N		+		+		+	agenesis of corpus callosum
83527	Norwegian-Indian	TMEM67	c. 755 T > C p.M252T	c. 2882 C > A p.S961Y^N	+	+		+
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.R1622FfsX9^N		+
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

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.

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ISSN: 2046-2530

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