Genetics

Molecular analysis by polymerase chain reaction (PCR) amplification followed by direct sequencing

MUSCOLAR DYSTROPHY AND  MYOPATHIES
Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD), DYS
Limb girdle muscular dystrophy
– Limb girdle muscular dystrophyLGMD1A, MYOT
– Limb girdle muscular dystrophy LGMD1B, LMNA
– Limb girdle muscular dystrophy LGMD1C, CAV3
– Limb girdle muscular dystrophy LGMD1E, DNAJB6
– Limb girdle muscular dystrophy LGMD2A, CAPN3
– Limb girdle muscular dystrophyLGMD2B, DYSF
– Limb girdle muscular dystrophy LGMD2C, SGCG
– Limb girdle muscular dystrophy LGMD2D, SGCA
– Limb girdle muscular dystrophy LGMD2E, SGCB
– Limb girdle muscular dystrophy LGMD2F, SGCD
– Limb girdle muscular dystrophy LGMD2I, FKRP
– Limb girdle muscular dystrophy LGMD2L, ANO5
Congenital muscular dystrophy MDC1A, LAMA2
Congenital muscular dystrophy MDC1C, FKRP
Muscular dystrophy (dystroglycan) type A7 (MDDGA7), ISPD
Congenital dystrophy:
–    Dystroglycan: POMT1, POMT2, POMGnT1, fukutina e LARGE.
Congenital myopathy:
–    Nemaline myopathy: NEB, KLHL40
–    Miofibrillar myopathy: DES, CRYAB, MYOT, ZASP e FLNC
Myoshi myopathy (MM), DYSF
Oculo-pharingeal myopathy (OPMD), PABPN1
Inner body myopathy (recessive forms), GNE
PCR detection of expanded alleles; long-range PCR and Southern blot for the identification of expanded alleles in Steiner Myotonic Dystrophy (MD1, DMPK), Myotonic Dystrophy, type 2 (MD2, ZNF9).

MUSCULAR CHANNELOPATHIES
Non-dystrophic myopathis
Congenital myotonia
– Thomsen Myotonia CLCN1
– Becker Myotonia, CLCN1
Sodium channel myotonia, SCN4A
Congenital paramyotonia, SCN4A
Periodic paralisis
– ipokaliemic periodic paralysis, CACNA1S, SCN4A
– iperkaliemic periodic paralysis, SCN4A
– Andersen-Tawil Syndrome, KCNJ2
Chlorine channel deficit, CLCN1

NEUROMUSCULAR DISORDERS
Congenital myasthenia
–    pre-synaptic forms: CHAT
–    synaptic forms: COLQ
–    post-synaptic forms: CHRNE, CHRNA1, RAPSN

NEURODEGENERATIVE DISORDERS
Familial Creutzfeldt-Jakob diasease, PRPN
Inner body myopathy, Paget’s diasese and frontotemporal dementia (IBMPFD), VCP
Wilson’s disease, ATP7B
Fronto-temporal dementia, PGRN
Fronto-temporal dementia, MAPT
Fronto-temporal dementia, CHMP2B
Leukoencephalopathy with trunk and spinal cord involvement and lactic acidosis (LBSL), DARS2
Alexander’s disease, GFAP
Alzheimer’s diseases, haplotype APOE

PARKINSON’S DISEASE
Autosomal and recessive forms.
Dominant: SNCA (PARK1), PARK8, LRRK2
Recessive: PARK2, PINK1, PARK7, DJ1’
Gene dosage by qPCR: SNCA (PARK1), PARK2.

MOTOR NEURON DISORDERS
Amyotrophic lateral sclerosis (ALS): SOD1, C9orf72, TARDBP, FUS/TLS, ANG, VAPB, UBQLN2, OPTN, VCP, PFN1, CHMP2B, SPG11
Spinal Amyotrophy with respiratory distress (SMARD1), IGHMBP2
Distal Spinal Amyotrophy type V, (DSMAV), GARS
Spinal Amyotrophy 5q, SMN1 e SMN2

HEREDITARY NEUROPATHIES
Polyneuropathy with amyloidosis, autosomal dominant, TTR
Charcot-Marie-Tooth disease type 2A (CMT2A), MFN2
Charcot-Marie-Tooth disease type 2D (CMT2D), GARS
Charcot-Marie-Tooth disease type 2B1 (CMT2B1), LMNA
Charcot-Marie-Tooth disease type 4A (CMT4A), GDAP1
Charcot-Marie-Tooth disease type 4J (CMT4J), FIG4
Charcot-Marie-Tooth X-linked (CMT1X), GJB1
Recurrent neuralgic amyotrophic (HNA), SEPT9

METABOLIC DISORDERS
Deficit di Carnitina Palmitoil-Trasferasi, CPT2
Glicogenosi di tipo 2, GAA
Glicogenosi di tipo 3, AGL
Glicogenosi di tipo 4, GBE1
Deficit di Mioadenilato Deaminasi, AMPD1
Deficit di Enolasi, ENO3

MITOCHONDRIAL DISEASES
Southern Blot of mitochondrial DNA
Direct sequencing of mitochondrial DNA (MitoSEQ) for the following phenotypes:
•    MELAS: tRNA Leu (A3243G)
•    MERRF: tRNA Lys (A8344G, G8363A, T8356C)
•    LHON (Leber Hereditary Optic Neuropathy): ND1 (G3460A), ND4 (G11778A), ND6 (T14484C)
•    NARP (and Leigh syndrome): ATPase 6 (T8993C/G, T9176C), ATPase 8
Long PCR for the identification of mitochondrial DNA rearrangements (single deletion, multiple deletions)
Quantitative PCR to assess mitochondrial DNA content
PCR-RFLP analysis of common mitochondrial disorders including:
•    MELAS: A3243G
•    MERRF: A8344G
•    NARP (and Leigh syndrome): T8993C/G, T9176C
Assembly factors of mitochondrial respiratory chain: SURF1 (Leigh Syndrome), SCO2 (mitochondrial encephalopathy), GFER, SDHAF1 (Leukodystrophy/Leukoecephalopathy), COX10 (Leigh Syndrome), COX15 (Leigh Syndrome)
Nuclear genes encoding for electron transfer proteins involved in fatty acids metabolism: ETFA, ETFB, ETFDH
Nuclear genes encoding for electron transfer proteins involved in mitochondrial DNA maintenance: POLG1, POLG2, ANT1, PEO1 (TWINKLE), RRM2B, TK2, DGUOK, MPV17, hDNA2, TYMP (Progressive External Ophthalmoplegia – PEO – featuring multiple mtDNA deletions, mitochondrial DNA depletion)
Nuclear genes encoding for electron transfer proteins involved in mitochondrial fusion pathway: OPA1, MFN2 (Dominat Optic Atrophy, DOA)




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