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

Mon Jan 2 09:53:19 EST 2017

Hi Megan

a bit in the same vein as Gigi, could these cases possibly have somewhat skewed inactivation of the healthy allele?

However, this thread also has me relook our adult WESed weird T cell penias, will tell you if we find any adult cases followed up, 

ATB

Mikko

Mikko Seppänen
Head
Hospital District of Helsinki and Uusimaa, Children's Hospital, Rare Disease Center 
P.O.Box 280, 00029 HUS |Lastenlinnantie 2, Helsinki
Senior Consultant
Hospital District of Helsinki and Uusimaa, Inflammation Center, Adult Primary Immunodeficiency Outpatient Clinic 
mikko.seppanen at hus.fi
+358 9 47180201| +358 50 4279606
faxi +358 9 47174703
www.hus.fi; www.harvinaissairaudet.fi 

-----Alkuperäinen viesti-----
Lähettäjä: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org] 
Lähetetty: 31. joulukuuta 2016 20:14
Vastaanottaja: CIS-PIDD <cis-pidd at lyris.dundee.net>
Aihe: RE: [cis-pidd] FOXN1 heterozygous phenotype?

Hi Megan,

We picked up a T-B+NK+ girl via TREC screening with a heterozygous FOXN1 mutation (targeted SCID panel). Normal exam, normal hair/nails. +Small amount of thymic tissue seen on ultrasound. Her T cell counts (~100) did not improve by 2.5 months of age.  Cord blood transplant was not successful and she awaits thymic transplant. 

We completed whole genome sequencing on the family quartet. Father and full sibling had the same FOXN1 mutation (we plan to immunophenotype and will try to get out-of-state TREC results on the older brother). No other significant pathogenic mutations in known PID genes except for a heterozygous mutation in ITGB2/CD18. 

We searched deeply for FOXN1 intronic variants upstream/downstream in the proband and mother, and nothing was found that would have fit an autosomal recessive inheritance pattern. 

I can send you more info if you'd like. Would be willing to share data per Gigi's email as well.

Best,
Karin

Karin Chen, MD
Assistant Professor
Department of Pediatrics
Division of Allergy & Immunology
University of Utah
karin.chen at hsc.utah.edu

________________________________________
From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
Sent: Friday, December 30, 2016 10:14 AM
To: CIS-PIDD
Cc: M Louise Markert, M.D., Ph.D.
Subject: Re: [cis-pidd] FOXN1 heterozygous phenotype?

I have a case in WI with predicted pathogenic and novel FOXN1 mutation not
found in parents and another mutation  which was maternal.  Baby picked up
with 0 TREC, T cell lymphopenia and low naïve T cells. No nail or hair
abnormalities.

We did WGS.  I agree it would be valuable to combine cases and review
genetics data.  As previously mentioned, Louise Markert has expressed an
interest in this.

Chris

Christine M. Seroogy MD,  FAAAAI
Associate Professor
University of Wisconsin School of Medicine and Public Health
Department of Pediatrics
Division of Allergy, Immunology & Rheumatology
1111 Highland Avenue
4139 WIMR
Madison, WI  53705-2275
phone: 608-263-2652
fax: 608-265-0164

On 12/30/16, 9:27 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=Dg
>>>>I
>>>>GaQ&c=Zoipt4Nmcnjorr_6TBHi1A&r=mERX_I8PKb0Uil9coedoT1CtvFqkSey45L0vbcX0
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>>>>Y
>>>>ChMemJbkOOltN-4w8rd7UQ&e=
>>>> (lab office) 314-286-0262
>>>> (lab fax) 314-286-2895
>>>>
>>>>
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