How do I know which genes are missing?

David March 5David decided to stand still so I could
take his picture.  Thanks David!

Originally posted 5 March 2016
Gene list corrections 6 March, 12 March, 17 June, 5 Dec 2016
Gene list correction 7 April 2017
Text edited 7 April 2021
Available in Portuguese http://pmsbrasil.org.br/como-saber-quais-genes-estao-faltando/

I often get asked to interpret a genetic report. I am not a clinician of any sort. I never even had a genetics course in college. But, there are certain skills one must pick up along the way to study which genes are missing in 22q13 deletion syndrome (Phelan-McDermid syndrome, PMS) and what they do. So, I have some idea how to read a report. Recently, I worked with Dr. Teresa Kohlenberg to create a page for PMS parents called: How to read a genetic report: examples from Phelan-McDermid syndrome (PMS).

If you have a genetic report it may not list which genes are missing. Often genetic reports only list “OMIM genes”. This list is not complete and it can be misleading. A good genetics consular may sit down with you and try to explain everything, but frankly only a geneticist can take it all in at once. If your child has a 22q13 deletion there are some ways you can find out which genes are missing on your own. This approach does not work in every case. Sometimes the genetic test itself is not precise enough. David had a FISH test 15 years ago. It is definitive for diagnosing PMS, but it is not sufficient to figure out which genes he is missing. If your child has a SHANK3 variant and no other genetic result, then you do not need to go looking for a list of genes. Only one gene is involved. If that seems unclear, read my blog The four types of Phelan McDermid syndrome

These days most children tested have a CMA (“array”) test and the following information will be helpful. I will cover different methods here. Often, the most practical method is to use the list of genes (see below). 

What experts do (Expert mode)

The experts use the technical part of a genetic report to see what has been deleted. The technical part will often look something like this. This nomenclature is explained in detail at the page How to read a genetic report.
hg17  arr 22q13.33 (48,230,183-49,523,149) X1
This example is a simple terminal deletion of chromosome 22 (not a real case).  It says that part of chromosome 22 only has one copy (X1). The nomenclature can get complicated, especially if there are multiple genetic problems. 

Once the expert knows which base-pairs are missing (48,230,183-49,523,149 in this case) and which genome assembly was used to make the measurement (hg17 in this case), he/she/they can go to the UCSC Genome Browser and get gobs of information about the deletion. The Genome Browser is complicated to use, but I use it often. It is densely packed with genetics information gathered from many sources. It can quickly provide a complete list of genes that are lost by a chromosomal deletion. 

Simplest

Sometimes a genetic report will provide a complete list of the missing genes.  “Complete” is relative to certain things. For instance, most gene array studies cannot detect the presence or loss of the last gene on the chromosome, RABL2B. This gene is too similar (in its sequence) to RABL2A and lax thinking about RABL2B has interfered with careful interpretation of its putative role in brain function. (See my blog Is 22q13 deletion syndrome a ciliopathy.) Otherwise, the gene list is useful. If the only genes listed are SHANK3 and ARSA, the deletion is very small or the list itself is far from complete. I am not a big fan of genetic reports that omit lots of information, even if a parent is not ready to absorb the information right away.

End gene or deletion size

If the deletion is a terminal deletion (the most common type), you can use the deletion size to look up the missing genes with the aid of my list (below).  If the report says something like, “from PLXNB2 to ACR” or “distal to” PLXNB2, then you can find PLXNB2 on the list and the deletion includes all the numbered genes lower than PLXNB2 (number 20 on the list). 

Go to the Foundation’s web site?

If you had 18q deletion syndrome, there is a site that was created for parents to look up the genes that are missing and what those genes do. No such site exists for 22q13. My blog is your best resource. 

Ask your geneticist

I have seen some very nice genetics reports with a complete list of genes deleted.  This is not always the case, but you might try asking your geneticist to supply a complete list of genes deleted. 

The list

Here is a list of the genes that covers the last 9.3 megabases (Mb) of 22q13. That is about the size of the largest known 22q13 terminal deletion. The list comes with a few caveats. First, deletions can be messy. Sometimes lots of genes are gone, then part of the next gene is also gone. People do not count half a gene. I usually add the partial gene to the list of missing genes, since the gene has been damaged at that point. Chromosomal microarrays (a.k.a. CMAs, arrays or gene chips) sample the chromosome every so often (every so many bases). It is not a continuous readout of the chromosome. Thus, in most cases, you don’t know the exact position of the break, but you will be given a number that is very close.  The DNA of a chromosome includes many things in addition to genes. It encodes things called microRNAs, promotors, inhibitors and enhancers. There are regions called “open reading frames”. The gene list I provide does not include these less-well studied regions of the chromosome. My list is limited to protein coding genes. Suffice it to say that a gene list tells only part of the story, but it is an important part. That said, this list comes without any warranty whatsoever. I take no responsibility for its use. It is part of a blog to educate parents. It is not a tool for legal, medical or any other practice. Ok?

The gene are number from the end of the chromosome. The deletion size value is the distance from the end of the gene to the end of the chromosome. For example, if your child has a terminal deletion of size 1 Mb (same as size 1,000 kb), then your child is missing one copy of the genes numbered 1 through 36. If the deletion size is 4.5 Mb, then the genes numbered 1 through 44 are deleted. 

 

#       Gene       Deletion size (kb)
1       RABL2B        34.81 
2       ACR           78.11 
3       SHANK3        85.17 
4       ARSA         195.14 
5       MAPK8IP2     206.92 
6       CHKB         235.47 
7       CPT1B        240.05 
8       SYCE3        255.56 
9       KLHDC7B      267.45 
10      ODF3B        286.65 
11      TYMP         288.47 
12      SCO2         292.86 
13      NCAPH2       295.00 
14      LMF2         310.78 
15      MIOX         328.43 
16      ADM2         332.03 
17      SBF1         343.44 
18      PPP6R2       373.38 
19      DENND6B      491.41 
20      PLXNB2       539.63 
21      MAPK11       548.08 
22      MAPK12       557.16 
23      HDAC10       567.21 
24      TUBGCP6      573.90 
25      SELO         600.85 
26      TRABD        618.90 
27      PANX2        638.18 
28      MOV10L1      656.85 
29      MLC1         733.11 
30      TTLL8        763.84 
31      IL17REL      809.78 
32      PIM3         854.39 
33      CRELD2       895.76 
34      ALG12        900.01 
35      ZBED4        928.39 
36      BRD1         995.26 
37      C22orf34     1,160.96 
38      FAM19A5      2,067.65 
39      TBC1D22A     3,642.77 
40      CERK         4,080.21 
41      GRAMD4       4,180.53 
42      CELSR1       4,281.30 
43      TRMU         4,484.77 
44      GTSE1        4,487.66 
45      TTC38        4,543.18 
46      PKDREJ       4,555.11 
47      CDPF1        4,570.18 
48      PPARA        4,620.06 
49      PRR34        4,764.32 
50      WNT7B        4,841.34 
51      ATXN10       4,973.16 
52      FBLN1        5,287.14 
53      RIBC2        5,385.97 
54      SMC1B        5,404.90 
55      FAM118A      5,508.30 
56      UPK3A        5,522.59 
57      KIAA0930     5,577.70 
58      NUP50        5,630.45 
59      PHF21B       5,809.48 
60      ARHGAP8      5,955.68 
61      PRR5         6,080.79 
62      LDOC1L       6,320.17 
63      KIAA1644     6,505.62
64      PARVG        6,610.00 
65      PARVB        6,649.55 
66      SAMM50       6,821.94 
67      PNPLA3       6,870.90 
68      PNPLA5       6,926.46 
69      SULT4A1      6,955.97 
70      EFCAB6       7,248.33 
71      MPPED1       7,310.62 
72      SCUBE1       7,475.08 
73      TTLL12       7,631.34 
74      TSPO         7,655.23 
75      MCAT         7,675.07 
76      BIK          7,688.76 
77      TTLL1        7,729.13 
78      PACSIN2      7,942.26 
79      ARFGAP3      7,961.07 
80      A4GALT       8,123.48 
81      ATP5L2       8,177.87 
82      CYB5R3       8,173.96 
83      RNU12        8,203.08 
84      POLDIP3      8,203.60 
85      SERHL2       8,260.06 
86      RRP7A        8,298.67 
87      SERHL        8,305.91 
88      NFAM1        8,386.07 
89      TCF20        8,603.03 
90      CYP2D6       8,688.56 
91      NDUFA6       8,727.69 
92      SMDT1        8,735.12 
93      FAM109B      8,739.03 
94      NAGA         8,747.64 
95      WBP2NL       8,785.70 
96      SEPT3        8,828.88 
97      CENPM        8,871.30 
98      TNFRSF13C    8,891.65 
99      SHISA8       8,903.80 
100     SREBF2       8,911.16 
101     CCDC134      8,992.58 
102     MEI1         9,019.01 
103     C22orf46     9,124.62 
104     NHP2L1(SNU13)9,129.56 
105     XRCC6        9,154.43 
106     DESI1        9,197.37 
107     PMM1         9,228.58 
108     CSDC2        9,241.80 
109     POLR3H       9,273.98 
110     ACO2         9,289.48 

That’s it. If you know the deletion size you can figure out which genes are missing. There are some cases of PMS where the deletion does not continue to the end of the chromosome (often called “interstitial deletions”). The list is still relevant, but identifying the genes in that (and other complex cases) requires a few more steps. For most families, using the list should be straightforward given a deletion size.

I want to thank the parents who have shared genetic reports and shared their own very personal stories. Your contributions and feedback help me feel that I am not alone in the quest to make the world a better place for our children.

 

arm22q13

 

Some previous blogs

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
22q13 deletion syndrome – an introduction

6 thoughts on “How do I know which genes are missing?

  1. I appreciate your knowledge. I appreciate your time and conversation when I found out about Miki’s second hit of ALG12 and the scientist that is studying the second hits in our kids, and the doctor that works at the same University as Dr Phelan. I appreciate your input as both a parent and as a scientist.

    Like

  2. Thank you, Andrew! This is very valuable, practical information. Our consult with the geneticist was useless – she told us Yulia’s deletion size was large (6.1 Mb) and when asked what that means we got “she’ll be OK.” True story. With your blog I can now actually make sense of the diagnosis and look up the 57 missing genes.

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  3. Thank you very much for putting so much effort and time!!! I absolutely love your blog.
    According to our report, Angie has a terminal deletion size of 3.5Mb.
    So all the genes, including some part of the TBC1D22A gene are deleted, right?
    The report says:
    arr 22q13.31q13.33(47,630,481×2, 47,664,055-51,178,235×1~2)

    What does the x2 or X1~2 stands for? I’m guessing it states which base parts she has 2 copies of, and which are missing.
    She has mosaic and ring22

    Thanks!!!!

    Like

    • It is times like this that I wish I had taken a course in cytogenetics. I am not a geneticist or a clinician of any sort. I read what I need to know as a go. The bit of info missing from your report is the genome assembly. The terminal deletion range matches with hg38, so I will assume we can use that build. I hope someone qualified will correct me if I am wrong, but I suspect 47,630,481×2 means that was the last spot on the chromosome where only normal (2 copies) of 22q13.33 was found. Arrays used to test sample the chromosome at various intervals (probes). So the probe at 47,630,481 read normal. Following that, apparently the next probe and all subsequent probes found either one copy or two copies, as you had surmised. I still have not verified the nomenclature X1-2, but I agree that is probably a mosaic. That is, in some samples they found x1 and other samples they found x2. (It may be calculated statistically rather than looking at samples from individual cells.) I cannot tell if some of the ch22 is normal and some ring. The mosaic suggests a somatic mutation (after fertilization) rather than a germ line mutation. The one thing that has me stumped is the deletion size of 3.5 MB. I would venture the deletion is 3,154,414. Practically speaking, it does not change the number of genes lost. However, that DNA may have other regulatory elements of importance. Your daughter has lost BRD1 which is a very important regulatory gene. It is probably far more important than SHANK3. A group out of Denmark is studying it and most of their work has not been published yet. It has a different impact on males than females.

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      • Thank you for the reply, and for excepting my friendship request 🙂
        They did several test, array and fish. Maybe the fish gave the ring result, I don’t remember.
        Anyway thank you for the info!
        And I would try to read more about BRD1.

        Like

  4. I don’t even know where to begin. This is amazing! This has helped more than you know. I so glad someone has taken time and put this into perspective for me. I’ve been wandering what all the genes mean. Thank you!

    Like

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