Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Yépez, Vicente A.; Gusic, Mirjana; Kopajtich, Robert; Mertes, Christian; Smith, Nicholas H.; Alston, Charlotte L.; Ban, Rui; Beblo, Skadi; Berutti, Riccardo; Blessing, Holger; Ciara, Elżbieta; Distelmaier, Felix; Freisinger, Peter; Häberle, Johannes; Hayflick, Susan J.; Hempel, Maja; Itkis, Yulia S.; Kishita, Yoshihito; Klopstock, Thomas; Krylova, Tatiana D.; Lamperti, Costanza; Lenz, Dominic; Makowski, Christine; Mosegaard, Signe; Müller, Michaela F.; Muñoz-Pujol, Gerard; Nadel, Agnieszka; Ohtake, Akira; Okazaki, Yasushi; Procopio, Elena; Schwarzmayr, Thomas; Smet, Joél; Staufner, Christian; Stenton, Sarah L.; Strom, Tim M.; Terrile, Caterina; Tort, Frederic; Van Coster, Rudy; Vanlander, Arnaud; Wagner, Matias; Xu, Manting; Fang, Fang; Ghezzi, Daniele; Mayr, Johannes A.; Piekutowska-Abramczuk, Dorota; Ribes, Antonia; Rötig, Agnès; Taylor, Robert W.; Wortmann, Saskia B.; Murayama, Kei; Meitinger, Thomas; Gagneur, Julien; Prokisch, Holger

doi:10.1186/s13073-022-01019-9

Table 1 Summary of cases diagnosed via RNA-seq. AE: aberrant expression, AS: aberrant splicing, MAE: mono-allelic expression, Var: intronic variant detected via RNA-seq. Variant coordinates and further details are provided in Additional file 1: Table S1

From: Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Index	Patient ID	Sex	Age range of onset	Primary symptoms	Genetic diagnosis	Variant RNA level	Variant class	RNA defects
1	R62943	F	Prenatal	Neurodevelopmental delay, 3-MGA	*C19orf70*	c.143del	Frameshift	AE, AS
1	R62943	F	Prenatal	Neurodevelopmental delay, 3-MGA	NM_205767.1	c.29+272G>C	Intronic
2	R98254	F	Infant	Leigh syndrome, basal ganglia abnormality MRI, neurodevelopmental delay, intellectual disability, seizures, encephalopathy, brainstem abnormality MRI, complex I and IV defects	*MRPL38*	c.770C>G	Missense	AE
2	R98254	F	Infant		NM_032478.3	c.-174_-148del	5′UTR deletion
3	R86287	M	Infant	Hypotonia, cardiomyopathy, white matter abnormality MRI, elevated lactate, complex I and IV defects	*DARS2*	c.492+2T>C	Splice donor	AS
3	R86287	M	Infant		NM_018122.4	c.228-12C>G; c.228-20T>C	Intronic multi-nucleotide variant (MNV)
4	R89912	M	Infant	Leigh syndrome, basal ganglia abnormality MRI, neurodevelopmental delay, speech delay, intellectual disability, encephalopathy, hypotonia, nystagmus, brainstem abnormality MRI, elevated lactate, metabolic acidosis, complex I defect	*NFU1*	c.362T>C	Missense	AE, MAE
4	R89912	M	Infant		NM_001002755.2	c.485-2588_545+1655del	Deletion
5	R19100	M	Child	Myopathic facies, exercise intolerance, muscle weakness, motor, growth, speech and neurodevelopmental delay, intellectual disability, microcephaly, hypotonia, cardiomyopathy, dysmorphic features, ragged red fibers, elevated lactate	*SLC25A4*	c.598G>A	Splice region	AE
5	R19100	M	Child		NM_001151.3	c.598G>A	Splice region
6	R15264	F	Infant	Muscle weakness, myopathy, muscular dystrophy, hypotonia	*TIMMDC1*	c.596+2146A>G	Intronic	AE, AS, Var
6	R15264	F	Infant	Muscle weakness, myopathy, muscular dystrophy, hypotonia	NM_016589.3	c.596+2146A>G	Intronic
7	R36605	M	Infant	Acute liver failure, hypotension of the muscles, hypertension of the limbs, intermittent deficiency of motor function of the pupil, delayed light reaction and nystagmus	*TWNK*	c.1302C>G	Synonymous	AE, AS
7	R36605	M	Infant		NM_001163812.1	c.1302C>G	Synonymous
8	R61100	F	Infant	Encephalopathy, respiratory distress	*NAXE*	c.292-12C>G	Intron	AE, AS
8	R61100	F	Infant	Encephalopathy, respiratory distress	NM_144772.2	c.292-12C>G	Intron
9	R77611	F	Infant	Recurrent acute liver failure	*DLD*	c.685G>T	Missense	AE, MAE
9	R77611	F	Infant	Recurrent acute liver failure	NM_000108.3
10	R16472	M	Child	Motor developmental delay, neurodevelopmental delay, respiratory distress, brainstem abnormality MRI, white matter abnormality MRI, leukoencephalopathy, elevated lactate, complex IV defect	*MRPS25*	c.329+75G>A	Intronic	AE, AS, Var
10	R16472	M	Child		NM_022497.4	c.329+75G>A	Intronic
11	R51757	M	Infant	Motor developmental delay, neurodevelopmental delay, seizures, feeding difficulties, elevated lactate, complex I defect	*NDUFA10*	c.-99_-75del	5′UTR	AE
11	R51757	M	Infant		NM_004544.3	c.-99_-75del	5′UTR
12	R80346	F	Birth	MDDS, seizures, encephalopathy, hypotonia, died as neonate, elevated lactate, complex III, IV and V defects	*LIG3*	c.86G>A	Stop	AE, Var
12	R80346	F	Birth		NM_002311.4	c.1611+208G>A	Intronic
13	R20754	M	Neonatal	Nystagmus, hearing impairment, white matter abnormality MRI	*UFM1*	c.-273_-271del	Promoter	AE
13	R20754	M	Neonatal	Nystagmus, hearing impairment, white matter abnormality MRI	NM_016617.2	c.-273_-271del	Promoter
14	R25473	F	Adult	Usher syndrome, immune abnormality, neutropenia, abnormality retina, cataract, visual impairment, hearing impairment	*PEX1*	c.1842del	Frameshift	AE, Var
14	R25473	F	Adult		NM_000466.2	c.1240-1551A>G	Intronic
15	R28774	M	Infant	Myopathy, neurodevelopmental delay, hypotonia, movement disorder, failure to thrive, feeding difficulties, died as a young child due to recurrent respiratory infections, complex I defect	*TIMMDC1*	c.596+2146A>G	Intronic	AE, AS, Var
15	R28774	M	Infant		NM_016589.3	c.596+2146A>G	Intronic
16	R96820	F	Neonatal	Muscle weakness, neurodevelopmental delay, hypotonia, microcephaly, cardiomyopathy, hearing impairment, elevated lactate, metabolic acidosis, complex IV defect	*CLPP*	c.661G>A	Splice region	AE, AS
16	R96820	F	Neonatal		NM_006012.2	c.661G>A	Splice region
17	R21147	M	Infant	Neurodevelopmental delay, feeding difficulties, elevated lactate, complex I defect	*NDUFA10*	c.-99_-75del	5′UTR	AE
17	R21147	M	Infant		NM_004544.3	c.-99_-75del	5′UTR
18	R64921	M	Child	Ophthalmoplegia, speech delay, developmental regression, ataxia, abnormality retina, visual impairment, complex I defect	*MCOLN1*	c.681-19A>C	Intronic	AE, AS
18	R64921	M	Child		NM_020533.2	c.832C>T	Stop
19	R52016	M	Infant	Died as infant, basal ganglia abnormality MRI, neurodevelopmental delay, encephalopathy, hypotonia, myoclonus, nystagmus, abnormality eye movement, neuropathy, brainstem abnormality MRI, elevated lactate, complex I defect	*TIMMDC1*	c.596+2146A>G	Intronic	AE, AS, Var
19	R52016	M	Infant		NM_016589.3	c.596+2146A>G	Intronic
20	R46723	F	Infant	Basal ganglia abnormality MRI, encephalopathy, brainstem abnormality MRI, complex I defect	*NDUFAF5*	c.2T>C	Start loss	AE, AS, Var
20	R46723	F	Infant		NM_024120.4	c.223-907A>C	Intronic
21	R58859	M	Adult	Ophthalmoplegia, myopathic facies, myalgia, diabetes, arrhythmias	*TAZ*	c.348C>T	Synonymous	AS
21	R58859	M	Adult		NM_181313	c.348C>T	Synonymous
22	R80184	M	Prenatal	Muscle weakness, myopathy, neurodevelopmental delay, intellectual disability, seizures, hypotonia, dystonia, spasticity, microcephaly, growth delay, failure to thrive, respiratory distress, cataract, abnormality eye movement, delayed myelination, hypoplasia of the corpus callosum, lack of insular opercularization, died as a young child from pneumonia, elevated lactate, complex I and I/III defects	*ALDH18A1*	c.1982C>A	Stop	AE, MAE
22	R80184	M	Prenatal		NM_001017423.1	c.1858C>T	Missense
23	R59185	F	Child	Basal ganglia abnormality MRI, ophthalmoplegia, ataxia, growth delay, arrhythmias, optic atrophy, visual impairment, neuropathy, white matter abnormality MRI, elevated lactate	*NDUFS4*	c.466_469dup	Frameshift	AE
23	R59185	F	Child		NM_002495.2	c.466_469dup	Frameshift
24	R63087	M	Child	Basal ganglia abnormality MRI, muscle weakness, myopathy, rhabdomyolysis, neurodevelopmental delay, seizures, infection related deterioration, elevated lactate	*SLC25A42*	c.380+2T>A	Splice donor	AS
24	R63087	M	Child		NM_178526.4	c.380+2T>A	Splice donor
25	R44456	F	Infant	MADD, respiratory distress, dysmorphic features	*MRPL44*	c.179+3A>G	Splice region	AE, AS
25	R44456	F	Infant	MADD, respiratory distress, dysmorphic features	NM_022915.3	c.179+3A>G	Splice region
26	R33391	F	Infant	Failure to thrive, elevated lactate, complex I defect	*NDUFAF5*	c.605dup	Frameshift	AS, Var
26	R33391	F	Infant	Failure to thrive, elevated lactate, complex I defect	NM_024120.4	c.223-907A>C	Intronic
27	R66696	M	Young child	Muscle weakness, myopathy, rhabdomyolysis, infection related deterioration, died as child, complex I, III and IV defects	*LPIN1*	c.2550-865_2667-34del	Deletion	AS
27	R66696	M	Young child		NM_001261427.1	c.2550-865_2667-34del	Deletion
28	R24289	M	Young child	Hypotonia, developmental delay, hearing impairment, white matter abnormality on MRI, lactic acidemia, hyperlactacidemia, proteinuria, glycosuria	*RRM2B*	c.328C>T	Missense	AE, MAE
28	R24289	M	Young child		NM_015713.4	c.?	Intergenic
29	R98349	F	Infant	Clotting defect, lactic acidosis	*DLD*	c.685G>T	Missense	AS
29	R98349	F	Infant	Clotting defect, lactic acidosis	NM_000108.5	c.1046+5G>T	Splice region
30	R91273	F	Adult	MADD during pregnancy	*ETFDH*	c.687_688del	Frameshift	AE
30	R91273	F	Adult	MADD during pregnancy	NM_004453.3	-
31	R60537	M	Neonatal	Congenital disorder of glycosylation, seizures, cognitive impairment, nose abnormalities, large fleshy ears, abnormal isoelectric focusing of serum transferrin	*ATP6AP1*	c.291-135C>T	Intronic	AE, Var
31	R60537	M	Neonatal		NM_00183.4	c.291-135C>T	Intronic
32	R70961	M	Young child	Leigh syndrome, optic atrophy, parkinsonism, status epilepticus, developmental regression, abnormal thalamic size, lactic acidosis, urinary glycosaminoglycan excretion	*PTCD3*	c.1519-1G>C	Splice acceptor	AS
32	R70961	M	Young child		NM_017952	c.1918C>G	Missense

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