[CIS PIDD] [cis-pidd] FOXN1 heterozygous phenotype?

Fri Dec 30 15:25:54 EST 2016

Thanks everyone.  We will test parents next.  The variant leads to an early stop codon, so I think we are confident it is haploinsufficiency.

The patient had a targeted SCID panel, so not WES.  I agree It will be very interesting to see if some of these cases with atypical presentation have genetic modifiers.

Best,

Megan

> On Dec 30, 2016, at 9:28 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
>
> I agree with Mike. However, we should not dismiss the possibility of
> digenic inheritance, where haploinsufficiency for FOXN1 - in combination
> with some other gene defect - may cause a phenotype. It would be great if
> would be willing to compare the WES data in all of these cases and see
> whether other changes are also shared, that could support a digenic
> inheritance. This has yet to be demonstrated in PIDs, but is well reported
> in other genetic conditions (such as nephropathies).
>
> Gigi
>
> Luigi D. Notarangelo, M.D.
> Deputy Chief, LHD
> Laboratory of Host Defenses
> DIR, NIAID, NIH, DHHS
> 10 Center Drive
> Bldg. 10 CRC, Room 5W3940
> Bethesda, MD 20892-1456
> Phone: 301-761-7550
> Fax: 301-480-3810
> cell: 301-272-0577
>
>
>
>
>
>
>> On 12/30/16, 10:09 AM, "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org> wrote:
>>
>> Hi Megan,
>>
>> Have the parents been sequenced?   I would question the pathogenicity of
>> the mutation if one of the parents were carriers and well.
>>
>> You might consider TCR spectratyping to see if there is any qualitative
>> abnormalities in the T cell repertoire.
>>
>> Best regards,
>> Mike
>>
>> Michael Keller MD
>> Assistant Professor
>> Childrens National Medical Center
>>
>>
>>> On Dec 30, 2016, at 9:34 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
>>> wrote:
>>>
>>> Megan - You should touch base with Elena Perez. She follows a leaky
>>> SCID patient (picked up be NBS) with FOXN1 mutation that was passed from
>>> the father.
>>>
>>> Jen Leiding
>>>
>>>
>>>
>>>
>>>> On 12/29/16, 10:16 PM, "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org>
>>>> wrote:
>>>>
>>>> Normal.
>>>>
>>>> CD19 - 957 cells/uL
>>>> CD56/16 - 766
>>>>
>>>> no other B cell phenotyping, but serum IgM was normal (36).
>>>>
>>>> Megan
>>>>
>>>> ________________________________________
>>>> From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
>>>> Sent: Thursday, December 29, 2016 9:09 PM
>>>> To: CIS-PIDD
>>>> Subject: Re: [cis-pidd] FOXN1 heterozygous phenotype?
>>>>
>>>> Hi Megan,
>>>> How are the B and NK cells?
>>>> Elie
>>>>
>>>> Élie Haddad,
>>>> CHU Ste-Justine,
>>>> University of Montreal, Canada
>>>>
>>>> On Dec 29, 2016, at 20:57, CIS-PIDD
>>>> <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
>>>> wrote:
>>>>
>>>>
>>>> Hi,
>>>>
>>>>
>>>>
>>>> I was wondering if anyone had seen a patient with T cell deficiency
>>>> due to a heterozygous FOXN1 deficiency?
>>>>
>>>>
>>>>
>>>> I'm seeing a 2mo male infant referred for low TREC on newborn screen
>>>> (~1/2 normal).  Initial CD3 count was ~900, and has subsequently
>>>> dropped to: CD3 - 543, CD4 - 403, CD8 - 121.  All other counts normal.
>>>> Proliferation to mitogens has been normal twice, and TREC copies per
>>>> CD3 cell was normal.  Slightly increased CD45RO for age (35%
>>>> CD4/CD45RO).  HIV negative, Chr22 FISH negative.
>>>>
>>>>
>>>>
>>>> A SCID gene panel showed a heterozygous FOXN1 variant leading to an
>>>> early stop codon (deletion/duplication analysis normal).  He does not
>>>> have alopecia universalis as reported in FOXN1 deficient patients.
>>>> For now we are monitoring closely, and trying to determine clinically
>>>> if there is a need for transplant. (which probably wouldn't be
>>>> helpful/needed if this were due to thymic defect with FOXN1).
>>>>
>>>>
>>>>
>>>> Thanks,
>>>>
>>>>
>>>>
>>>> Megan
>>>>
>>>>
>>>>
>>>>
>>>> Megan A. Cooper, MD, PhD
>>>> Assistant Professor, Department of Pediatrics
>>>> Division of Rheumatology
>>>> Washington University School of Medicine
>>>> Cooper_m at kids.wustl.edu<mailto:Cooper_m at kids.wustl.edu>
>>>> Lab website:
>>>> https://urldefense.proofpoint.com/v2/url?u=http-3A__research.peds.wustl.
>>>> edu_Default.aspx-3Falias-3Dresearch.peds.wustl.edu_Labs_Cooper-5FM&d=DgI
>>>> GaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1CtvFqkSey45L0vbcX0o
>>>> KI&m=p0bF-HJN5_so5edQKkTbLExoepDHZ4LdCR9lwI0_o6o&s=T2tFj7m9yjFL4v2QPbPUY
>>>> ChMemJbkOOltN-4w8rd7UQ&e=
>>>> (lab office) 314-286-0262
>>>> (lab fax) 314-286-2895
>>>>
>>>>
>>>>
>>>>
>>>> The materials in this email are private and may contain Protected
>>>> Health Information. If you are not the intended recipient, be advised
>>>> that any unauthorized use, disclosure, copying, distribution or the
>>>> taking of any action in reliance on the contents of this information is
>>>> strictly prohibited. If you have received this email in error, please
>>>> immediately notify the sender via telephone or return email.
>>>>
>>>> ---
>>>>
>>>> You are currently subscribed to cis-pidd as:
>>>> elie.haddad at umontreal.ca<mailto:elie.haddad at umontreal.ca>.
>>>>
>>>> To unsubscribe click here:
>>>> https://urldefense.proofpoint.com/v2/url?u=http-3A__cts.dundee.net_u-3Fi
>>>> d-3D96396514.54eb7da7d93cf91f012ad7a90560a39a-26n-3DT-26l-3Dcis-2Dpidd-2
>>>> 6o-3D4098139&d=DgIGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1C
>>>> tvFqkSey45L0vbcX0oKI&m=p0bF-HJN5_so5edQKkTbLExoepDHZ4LdCR9lwI0_o6o&s=iOe
>>>> C1uMxkJCNOGeTwx4lxe1VIkHeWdpr8tqhCq5UKnI&e=
>>>>
>>>> (It may be necessary to cut and paste the above URL if the line is
>>>> broken)
>>>>
>>>> or send a blank email to
>>>> leave-4098139-96396514.54eb7da7d93cf91f012ad7a90560a39a at lyris.dundee.net
>>>> <mailto:leave-4098139-96396514.54eb7da7d93cf91f012ad7a90560a39a at lyris.du
>>>> ndee.net>
>>>>
>>>> ---
>>>> You are currently subscribed to cis-pidd as: cooper_m at kids.wustl.edu.
>>>> To unsubscribe click here:
>>>> https://urldefense.proofpoint.com/v2/url?u=http-3A__cts.dundee.net_u-3Fi
>>>> d-3D96396471.9a016f51f09faba79ab9575dbdcfbf77-26n-3DT-26l-3Dcis-2Dpidd-2
>>>> 6o-3D4098148&d=DgIGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1C
>>>> tvFqkSey45L0vbcX0oKI&m=p0bF-HJN5_so5edQKkTbLExoepDHZ4LdCR9lwI0_o6o&s=YgC
>>>> VG4SeNaEAEtgtbqLLJS2nTQHZvDVIVAJo23PhV9A&e=
>>>> or send a blank email to
>>>> leave-4098148-96396471.9a016f51f09faba79ab9575dbdcfbf77 at lyris.dundee.net
>>>> ---
>>>> You are currently subscribed to cis-pidd as: jleiding at health.usf.edu.
>>>> To unsubscribe click here:
>>>> https://urldefense.proofpoint.com/v2/url?u=http-3A__cts.dundee.net_u-3Fi
>>>> d-3D96396677.8032d543d21ea0e17bb1a686e8069e36-26n-3DT-26l-3Dcis-2Dpidd-2
>>>> 6o-3D4098154&d=DgIGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1C
>>>> tvFqkSey45L0vbcX0oKI&m=p0bF-HJN5_so5edQKkTbLExoepDHZ4LdCR9lwI0_o6o&s=6j4
>>>> 0iQ3I728LwdF1iFRHSNjc6K2EkttL8locSgvlkR0&e=
>>>> or send a blank email to
>>>> leave-4098154-96396677.8032d543d21ea0e17bb1a686e8069e36 at lyris.dundee.net
>>>
>>> ---
>>> You are currently subscribed to cis-pidd as:
>>> mkeller at childrensnational.org.
>>> To unsubscribe click here:
>>> https://urldefense.proofpoint.com/v2/url?u=http-3A__cts.dundee.net_u-3Fid
>>> -3D103356975.2feedb0edc55e38c9c805588973b0280-26n-3DT-26l-3Dcis-2Dpidd-26
>>> o-3D4098818&d=DgIGaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1Ctv
>>> FqkSey45L0vbcX0oKI&m=p0bF-HJN5_so5edQKkTbLExoepDHZ4LdCR9lwI0_o6o&s=uex7Qx
>>> dfCQJRQ49zWexMgCICkB-kZDS8ygQpIi_rLbo&e=
>>> or send a blank email to
>>> leave-4098818-103356975.2feedb0edc55e38c9c805588973b0280 at lyris.dundee.net
>>
>> ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
>> Confidentiality Notice: This e-mail message, including any attachments,
>> is for the sole use of the intended recipient(s) and may contain
>> confidential and privileged information. Any unauthorized review, use,
>> disclosure or distribution is prohibited. If you are not the intended
>> recipient, please contact the sender by reply e-mail and destroy all
>> copies of the original message.
>>
>> ---
>> You are currently subscribed to cis-pidd as: luigi.notarangelo2 at nih.gov.
>> To unsubscribe click here:
>> http://cts.dundee.net/u?id=96396777.ceaf29f3e714b483a0a5aecd8ad92646&n=T&l
>> =cis-pidd&o=4098853
>> or send a blank email to
>> leave-4098853-96396777.ceaf29f3e714b483a0a5aecd8ad92646 at lyris.dundee.net
>
>
> ---
> You are currently subscribed to cis-pidd as: cooper_m at kids.wustl.edu.
> To unsubscribe click here: http://cts.dundee.net/u?id=96396471.9a016f51f09faba79ab9575dbdcfbf77&n=T&l=cis-pidd&o=4098882
> or send a blank email to leave-4098882-96396471.9a016f51f09faba79ab9575dbdcfbf77 at lyris.dundee.net

The materials in this email are private and may contain Protected Health Information. If you are not the intended recipient, be advised that any unauthorized use, disclosure, copying, distribution or the taking of any action in reliance on the contents of this information is strictly prohibited. If you have received this email in error, please immediately notify the sender via telephone or return email.

---
You are currently subscribed to cis-pidd as: pagid at list.clinimmsoc.org.
To unsubscribe click here: http://cts.dundee.net/u?id=96396833.5a9591ccd1e327fe6bc4d1543298c482&n=T&l=cis-pidd&o=4099216
or send a blank email to leave-4099216-96396833.5a9591ccd1e327fe6bc4d1543298c482 at lyris.dundee.net