Methods for diagnosing autism spectrum disorders

• US 10,655,178 B2
• Filed: 11/30/2017
• Issued: 05/19/2020
• Est. Priority Date: 09/08/2009
• Status: Active Grant

• Current Assignee: Laboratory Corporation Of America Holdings
• Original Assignee: Laboratory Corporation Of America Holdings
• Inventors: Margulies, David Michael, Bear, Mark Firman
• Primary Examiner(s): Mahatan, Channing S
• Application Number:
  US15/827,044
• Publication Number:
  US 20180112269A1
• Time in Patent Office: 901 Days
• Field of Search: None
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/178 miRNA, siRNA or ncRNA

Abstract

The invention generally relates to methods for diagnosing autism spectrum disorders. In certain embodiments, the invention provides a method for diagnosing presence or increased risk of developing an autism spectrum disorder in a subject.

Claims

1. A method for detecting a mutation associated with the presence or an increased risk of developing an autism spectrum disorder in a subject, the method comprising:

obtaining a nucleic acid from a tissue or body fluid sample from a subject; and

conducting an assay to identify whether there is at least one of a TSC1 or a TSC2 variant sequence in the subject'"'"'s nucleic acid;

(i) wherein for TSC1 the variant sequences comprise at least one of;

c.346T>

G, Leu116Val;

c.935A>

C, Tyr312Ser;

c.1006C>

T, Arg336Trp;

c.1178C>

T, Thr393Ile;

c.1523A>

C, Tyr508Ser;

c.1559A>

C, His520Pro;

c.1580A>

G, Gln527Arg;

c.1608A>

C, Leu536Phe;

c.1610A>

C, His537Pro;

c.1683T>

G, Ser561Arg;

c.1781T>

G, Val594Gly;

c.1799A>

C, Gln600Pro;

c.1829T>

G, Val610Gly;

c.1843A>

C, Thr615Pro;

c.1844C>

A, Thr615Lys;

c.1917T>

G, Gly639Gly;

c.1943T>

G, Val648Gly;

c.1958T>

G, Ile653Arg;

c.1960C>

A, Gln654Lys;

c.1960C>

G, Gln654Glu;

c.1963C>

A, Gln655Lys;

c.1997+2T>

G (splice site);

c.2194C>

T, His732Tyr;

c.2865C>

T, Thr955Thr;

c.3042C>

T, His1014His;

c.3059C>

T, Thr1020Ile;

c.3102T>

G, Gly1034Gly;

or c.3105T>

G, Gly1035Gly; and

(ii) wherein for TSC2 the variant sequences comprise at least one of;

c.275A>

T, Glu92Val;

c.433G>

A, Ala145Thr;

c.649-5A>

C, (intronic);

c.736A>

C, Thr246Pro;

c.796A>

C, Thr266Pro;

c.848+15T>

G, (intronic);

c.1292C>

T, Ala431Val;

c.1875A>

C, Ser625Ser;

c.3126G>

T, Pro1042Pro;

c.3299T>

G, Val1100Gly;

c.3778A>

C, Thr1260Pro;

c.3827C>

T, Ser1276Phe;

c.3914C>

T, Pro1305Leu;

c.3986G>

A, Arg1329His;

c.4006-8C>

T, (intronic);

c.4051G>

A, Glu1351Lys;

c.4269G>

A, Leu1423Leu;

c.4285G>

T, Ala1429Ser;

c.4990-7C>

T, (intronic);

c.5028G>

A, Leu1676Leu;

c.5069-8C>

T, (intronic);

c.5359G>

A, Gly1787Ser;

or c.5429G>

A, (3′

UTR).

2. The method according to claim 1, wherein the assay comprises at least one of nucleic acid sequencing, hybrid capture, and epigenetic analysis.

3. The method according to claim 2, wherein the nucleic acid sequencing comprises at least one of single-molecule sequencing-by-synthesis or massively parallel sequencing.

4. The method according to claim 2, wherein a plurality of DNA samples are analyzed in a pool to identify samples that show a variation.

5. The method according to claim 4, wherein a plurality of DNA samples are analyzed in a plurality of pools to identify an individual sample that shows the same variation in at least two pools.

6. The method according to claim 1, further comprising conducting an assay to identify whether there is an additional variant sequence in at least one of MECP2, SHANK3, GRAIL GRM5, ARC, EIF4E, HOMER1, HRAS, MAP2K1, MAP2K2, RAF1, PIK3CA, PIK3R1, FMR1, PTEN, RHEB or UBE3A.

7. The method according to claim 6, wherein the variant comprises at least one of the following variants:

8. The method according to claim 6, wherein the variant comprises at least one of the following mutations:

HOMER 1 c.195G>

T, M65I;

HOMER 1 c.290C>

T, S97L;

HOMER 1 c.425C>

T, P142L;

GRM5 c.3503T>

C, L1168P;

MAPK2 c.581-1G>

T;

HRAS c.383G>

A, R128Q;

a or MECP2 c.1477G>

T, E483X.

9. The method according to claim 1, further comprising conducting an assay to identify whether there is an additional variant sequence in SHANK3 and HOMER1.

10. The method according to claim 1, wherein the autism spectrum disorder comprises non-syndromic autism.

11. The method according to claim 10, wherein the autism spectrum disorder further comprises at least one of classical autism, Asperger'"'"'s syndrome, Rett'"'"'s syndrome, childhood disintegrative disorder, or pervasive developmental disorder not otherwise specified (PDD-NOS).

12. The method according to claim 1, further comprising diagnosing the presence of, or an increased risk of developing, a genetic syndrome linked to autism, wherein the genetic syndrome comprises fragile X syndrome.

13. The method according to claim 12, wherein the genetic syndrome further comprises at least one of Angelman syndrome, Prader-Willi syndrome, 15q11-q13 duplication, fragile X premutation, deletion of chromosome 2q, XYY syndrome, Smith-Lemli-Opitz syndrome, Apert syndrome, mutations in the ARX gene, De Lange syndrome, Smith-Magenis syndrome, Williams syndrome, Noonan syndrome, Down syndrome, velo-cardio-facial syndrome, myotonic dystrophy, Steinert disease, tuberous sclerosis, Duchenne'"'"'s disease, Timothy syndrome, 10p terminal deletion, Cowden syndrome, 45,X/46,XY mosaicism, Myhre syndrome, Sotos syndrome, Cohen syndrome, Goldenhar syndrome, Joubert syndrome, Lujan-Fryns syndrome, Moebius syndrome, hypomelanosis of Ito, neurofibromatosis type 1, CHARGE syndrome, or HEADD syndrome.

14. The method according to claim 1, wherein the subject is a child.

15. The method according to claim 1, wherein the subject is a fetus.

16. The method according to claim 1, wherein the body fluid comprise at least one of cerebrospinal fluid, blood, amniotic fluid, maternal blood, and urine.