David 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.
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.
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.
Some previous blogs
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